recent journal articles: immunology




Recent Articles in Annual Review of Immunology

Malek TR
The Biology of Interleukin-2.
Annu Rev Immunol. 2007 Dec 6;
Much data support an essential role for interleukin (IL)-2 in immune tolerance. This idea is much different from the early paradigm in which IL-2 is central for protective immune responses. This change in thinking occurred when a T regulatory cell defect was shown to be responsible for the lethal autoimmunity associated with IL-2/IL-2R deficiency. This realization allowed investigators to explore immune responses in IL-2-nonresponsive mice rendered autoimmune-free. Such studies established that IL-2 sometimes contributes to optimal primary immune responses, but it is not mandatory. Emerging findings, however, suggest an essential role for IL-2 in immune memory. Here, the current understanding of the dual role of IL-2 in maintaining tolerance and contributing to immunity in vivo is reviewed with some emphasis on T regulatory cell production and homeostasis. Also discussed are implications of this new appreciation concerning the immunobiology of IL-2 with respect to targeting IL-2 or its receptor in immunotherapy. Expected final online publication date for the Annual Review of Immunology Volume 26 is March 19, 2008. Please see for revised estimates. [Abstract]

Randolph GJ, Ochando J, Partida-S Nchez S
Migration of Dendritic Cell Subsets and their Precursors.
Annu Rev Immunol. 2007 Nov 28;
blacksquare, square, filled Abstract The ability of dendritic cells (DCs) to initiate and orchestrate immune responses is a consequence of their localization within tissues and their specialized capacity for mobilization. The migration of a given DC subset is typified by a restricted capacity for recirculation, contrasting markedly with T cells. Routes of DC migration into lymph nodes differ notably for distinct DC subsets. Here, we compare the distinct migratory patterns of plasmacytoid DCs (pDCs), CD8alpha + DCs, Langerhans cells, and conventional myeloid DCs and discuss how the highly regulated patterns of DC migration in vivo may affect their roles in immunity. Finally, to gain a more molecular appreciation of the specialized migratory properties of DCs, we review the signaling cascades that govern the process of DC migration. Expected final online publication date for the Annual Review of Immunology Volume 26 is March 19, 2008. Please see for revised estimates. [Abstract]

Spolski R, Leonard WJ
Interleukin-21: Basic Biology and Implications for Cancer and Autoimmunity.
Annu Rev Immunol. 2007 Nov 8;
blacksquare, square, filled Abstract Interleukin-21 (IL-21), a potent immunomodulatory four-alpha-helicalbundle type I cytokine, is produced by NKT and CD(4+) T cells and has pleiotropic effects on both innate and adaptive immune responses. These actions include positive effects such as enhanced proliferation of lymphoid cells, increased cytotoxicity of CD(8+) T cells and natural killer (NK) cells, and differentiation of B cells into plasma cells. Conversely, IL-21 also has direct inhibitory effects on the antigen-presenting function of dendritic cells and can be proapoptotic for B cells and NK cells. IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development. The regulatory activity of IL-21 is modulated by the differentiation state of its target cells as well as by other cytokines or costimulatory molecules. IL-21 has potent antitumor activity but is also associated with the development of autoimmune disease. IL-21 transcription is dependent on a calcium signal and NFAT sites, and IL-21 requires Stat3 for its signaling. The key to harnessing the power of IL-21 will depend on better understanding its range of biological actions, its mechanism of action, and the molecular basis of regulation of expression of IL-21 and its receptor. Expected final online publication date for the Annual Review of Immunology Volume 26 is March 19, 2008. Please see for revised estimates. [Abstract]

Vidal SM, Malo D, Marquis JF, Gros P
Forward Genetic Dissection of Immunity to Infection in the Mouse.
Annu Rev Immunol. 2007 Oct 22;
blacksquare, square, filled Abstract Forward genetics is an experimental approach in which gene mapping and positional cloning are used to elucidate the molecular mechanisms underlying phenotypic differences between two individuals for a given trait. This strategy has been highly successful for the study of inbred mouse strains that show differences in innate susceptibility to bacterial, parasitic, fungal, and viral infections. Over the past 20 years, these studies have led to the identification of a number of cell populations and critical biochemical pathways and proteins that are essential for the early detection of and response to invading pathogens. Strikingly, the macrophage is the point of convergence for many of these genetic studies. This has led to the identification of diverse pathways involved in extracellular and intracellular pathogen recognition, modification of the properties and content of phagosomes, transcriptional response, and signal transduction for activation of adaptive immune mechanisms. In models of viral infections, elegant genetic studies highlighted the pivotal role of natural killer cells in the detection and destruction of infected cells. Expected final online publication date for the Annual Review of Immunology Volume 26 is March 19, 2008. Please see for revised estimates. [Abstract]

Austen KF
Doing What I Like.
Annu Rev Immunol. 2007 Sep 17;
blacksquare, square, filled Abstract I have spent my entire professional life at Harvard Medical School, beginning as a medical student. I have enjoyed each day of a diverse career in four medical subspecialties while following the same triad of preclinical areas of investigation-cysteinyl leukotrienes, mast cells, and complement-with occasional translational opportunities. I did not envision a career with a predominant preclinical component. Such a path simply evolved because I chose instinctively at multiple junctures to follow what proved to be propitious opportunities. My commentary notes some of the highlights for each area of interest and the mentors, collaborators, and trainees whose counsel has been immensely important at particular intervals or over an extended period. Expected final online publication date for the Annual Review of Immunology Volume 26 is March 19, 2008. Please see for revised estimates. [Abstract]

Hislop AD, Taylor GS, Sauce D, Rickinson AB
Cellular responses to viral infection in humans: lessons from Epstein-Barr virus.
Annu Rev Immunol. 2007;25587-617.
Epstein-Barr virus (EBV) provides a useful model to study cellular immunity to a genetically stable, persistent human virus. Different sets of proteins expressed during EBV's lytic and cell transforming infections induce qualitatively different cellular immune responses. The factors governing immunodominance hierarchies and the biological effectiveness of these different responses are now being revealed. Analysis of infectious mononucleosis (IM), a clinical syndrome that can arise during primary EBV infection, has allowed the evolution of the responses to be tracked over time, giving an understanding of the immune response kinetics and of those determinants affecting selection into memory. Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals. This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community. [Abstract]

Marshak-Rothstein A, Rifkin IR
Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease.
Annu Rev Immunol. 2007;25419-41.
Pattern recognition receptors (PRRs), expressed on cells of both the innate and adaptive immune systems, serve as sentinels, waiting to alert the host to the first signs of microbial infection and to activate the initial line of immune defense. Research has increasingly demonstrated that many of the same PRRs also recognize self-epitopes that either are released from dying or damaged cells or are present at the surface of apoptotic cells or apoptotic bodies. In this context, PRRs play a critical role in tissue repair and the clearance of cellular debris. However, failure to appropriately regulate self-responses triggered by certain PRRs can have serious pathological consequences. The Toll-like receptor (TLR) gene family represents a case in point. TLR7, 8, and 9 were originally identified as receptors specific for bacterial and viral RNA and DNA, but more recent in vitro and in vivo studies have now linked these receptors to the detection of host RNA, DNA, and RNA- or DNA-associated proteins. In this context, they likely play a key role in the development of systemic autoimmune diseases. [Abstract]

Iwasaki A
Mucosal dendritic cells.
Annu Rev Immunol. 2007;25381-418.
The internal surfaces of the human body are covered by distinct types of epithelial cells and mucus-secreting cells. The mucosal surfaces serve many vital functions, such as respiration (nasal passage and lung), absorption (gastrointestinal tract), excretion (lung, urinary tract, large intestine), and reproduction (reproductive tract). In performing these functions, the host is inevitably exposed to environmental antigens, food particles, commensal flora, and pathogens. Mucosal surfaces contain specialized dendritic cells (DCs) capable of sensing these external stimuli and mounting appropriate local responses depending on the nature of the elements they encounter. In the absence of pathogens, mucosal DCs either ignore the antigen or induce regulatory responses. Upon recognition of microorganisms that invade the mucosal barrier, mucosal DCs mount robust protective immunity. This review highlights progress in our understanding of how mucosal DCs process external information and direct appropriate responses by mobilizing various cells of the innate and adaptive immune systems to achieve homeostasis and protection. [Abstract]

Davis MM, Krogsgaard M, Huse M, Huppa J, Lillemeier BF, Li QJ
T cells as a self-referential, sensory organ.
Annu Rev Immunol. 2007;25681-95.
In light of recent data showing that both helper and cytotoxic T cells can detect even a single molecule of an agonist peptide-MHC, alphabeta T cells are clearly a type of sensory cell, comparable to any in the nervous system. In addition, endogenous (self) peptides bound to MHCs are not just important for thymic selection, but also play an integral role in T cell activation in the response to foreign antigens. With the multitude of specificities available to most T cells, they can thus be considered as a sensory organ, trained on self-peptide-MHCs and primed to detect nonself. [Abstract]

Pao LI, Badour K, Siminovitch KA, Neel BG
Nonreceptor protein-tyrosine phosphatases in immune cell signaling.
Annu Rev Immunol. 2007;25473-523.
Tyrosyl phosphorylation plays a critical role in multiple signaling pathways regulating innate and acquired immunity. Although tyrosyl phosphorylation is a reversible process, we know much more about the functions of protein-tyrosine kinases (PTKs) than about protein-tyrosine phosphatases (PTPs). Genome sequencing efforts have revealed a large and diverse superfamily of PTPs, which can be subdivided into receptor-like (RPTPs) and nonreceptor (NRPTPs). The role of the RPTP CD45 in immune cell signaling is well known, but those of most other PTPs remain poorly understood. Here, we review the mechanism of action, regulation, and physiological functions of NRPTPs in immune cell signaling. Such an analysis indicates that PTPs are as important as PTKs in regulating the immune system. [Abstract]

Allen SJ, Crown SE, Handel TM
Chemokine: receptor structure, interactions, and antagonism.
Annu Rev Immunol. 2007;25787-820.
Chemokines are critical mediators of cell migration during routine immune surveillance, inflammation, and development. Chemokines bind to G protein-coupled receptors and cause conformational changes that trigger intracellular signaling pathways involved in cell movement and activation. Although chemokines evolved to benefit the host, inappropriate regulation or utilization of these proteins can contribute to or cause many diseases. Specific chemokine receptors provide the portals for HIV to get into cells, and others contribute to inflammatory diseases and cancer. Thus, there is significant interest in developing receptor antagonists. To this end, the structures of ligands coupled with mutagenesis studies have revealed mechanisms for antagonism based on modified proteins. Although little direct structural information is available on the receptors, binding of small molecules to mutant receptors has allowed the identification of key residues involved in the receptor-binding pockets. In this review, we discuss the current knowledge of chemokine:receptor structure and function, and its contribution to drug discovery. [Abstract]

Petrie HT, Zúñiga-Pflücker JC
Zoned out: functional mapping of stromal signaling microenvironments in the thymus.
Annu Rev Immunol. 2007;25649-79.
All hematopoietic cells, including T lymphocytes, originate from stem cells that reside in the bone marrow. Most hematopoietic lineages also mature in the bone marrow, but in this respect, T lymphocytes differ. Under normal circumstances, most T lymphocytes are produced in the thymus from marrow-derived progenitors that circulate in the blood. Cells that home to the thymus from the marrow possess the potential to generate multiple T and non-T lineages. However, there is little evidence to suggest that, once inside the thymus, they give rise to anything other than T cells. Thus, signals unique to the thymic microenvironment compel multipotent progenitors to commit to the T lineage, at the expense of other potential lineages. Summarizing what is known about the signals the thymus delivers to uncommitted progenitors, or to immature T-committed progenitors, to produce functional T cells is the focus of this review. [Abstract]

Kastelein RA, Hunter CA, Cua DJ
Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation.
Annu Rev Immunol. 2007;25221-42.
Long-term resistance to many infections depends on the innate ability of the immune system to coordinate the development of antigen-specific adaptive responses. Deficiencies in these events can result in increased susceptibility to pathogens, whereas an inability to regulate an appropriate response can lead to devastating pathological conditions. For over a decade, interleukin (IL)-12 has been recognized as the canonical cytokine that links innate and adaptive immunity, and with the discovery of IL-23 and IL-27 as cytokines related to IL-12, there has been a concerted effort to understand the relationship between these factors. The results emerging from these studies have provided fundamental new insights into the developmental pathways that promote the differentiation and function of CD4(+) T helper cells and offer a dramatically altered perspective on the cause and prevention of autoimmune disease. In this review, we aim to highlight the discoveries that have led to our current understanding of the biology of IL-23 and IL-27 in the context of their role in resistance to infection, immune-mediated inflammation, and cancer. [Abstract]

Chen J, Subbarao K
The Immunobiology of SARS*.
Annu Rev Immunol. 2007;25443-72.
Severe acute respiratory syndrome (SARS) presented as an atypical pneumonia that progressed to acute respiratory distress syndrome in approximately 20% of cases and was associated with a mortality of about 10%. The etiological agent was a novel coronavirus (CoV). Angiotensin-converting enzyme 2 is the functional receptor for SARS-CoV; DC-SIGN and CD209L (L-SIGN) can enhance viral entry. Although the virus infects the lungs, gastrointestinal tract, liver, and kidneys, the disease is limited to the lungs, where diffuse alveolar damage is accompanied by a disproportionately sparse inflammatory infiltrate. Pro-inflammatory cytokines and chemokines, particularly IP-10, IL-8, and MCP-1, are elevated in the lungs and peripheral blood, but there is an unusual lack of an antiviral interferon (IFN) response. The virus is susceptible to exogenous type I IFN but suppresses the induction of IFN. Innate immunity is important for viral clearance in the mouse model. Virus-specific neutralizing antibodies that develop during convalescence prevent reinfection in animal models. [Abstract]

Ma CS, Nichols KE, Tangye SG
Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules.
Annu Rev Immunol. 2007;25337-79.
SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states. [Abstract]

Davis RS
Fc receptor-like molecules.
Annu Rev Immunol. 2007;25525-60.
Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21-23 chromosomal region and revealed significant diversity for these genes between humans and mice. The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements. In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression. Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors. These characteristics, in addition to their identification in malignancies and autoimmune disorders, predict a fundamental role for these receptors as immunomodulatory agents in normal and subverted B lineage cells. [Abstract]

Luo BH, Carman CV, Springer TA
Structural basis of integrin regulation and signaling.
Annu Rev Immunol. 2007;25619-47.
Integrins are cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 A couple to conformational change in ligand-binding sites and are linked to changes in alpha and beta subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics. [Abstract]

Lemaitre B, Hoffmann J
The host defense of Drosophila melanogaster.
Annu Rev Immunol. 2007;25697-743.
To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them. [Abstract]

Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H
The death domain superfamily in intracellular signaling of apoptosis and inflammation.
Annu Rev Immunol. 2007;25561-86.
The death domain (DD) superfamily comprising the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily, and the pyrin domain (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfamily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular interactions mediated by them. By analyzing the potential molecular basis for the function of these domains, we hope to provide a comprehensive understanding of the function, structure, interaction, and evolution of this important family of domains. [Abstract]

Cumano A, Godin I
Ontogeny of the hematopoietic system.
Annu Rev Immunol. 2007;25745-85.
Blood cells are constantly produced in the bone marrow (BM) of adult mammals. This constant turnover ultimately depends on a rare population of progenitors that displays self-renewal and multilineage differentiation potential, the hematopoietic stem cells (HSCs). It is generally accepted that HSCs are generated during embryonic development and sequentially colonize the fetal liver, the spleen, and finally the BM. Here we discuss the experimental evidence that argues for the extrinsic origin of HSCs and the potential locations where HSC generation might occur. The identification of the cellular components playing a role in the generation process, in these precise locations, will be important in understanding the molecular mechanisms involved in HSC production from undifferentiated mesoderm. [Abstract]

Weaver CT, Hatton RD, Mangan PR, Harrington LE
IL-17 family cytokines and the expanding diversity of effector T cell lineages.
Annu Rev Immunol. 2007;25821-52.
Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense. [Abstract]

Bendelac A, Savage PB, Teyton L
The biology of NKT cells.
Annu Rev Immunol. 2007;25297-336.
Recognized more than a decade ago, NKT cells differentiate from mainstream thymic precursors through instructive signals emanating during TCR engagement by CD1d-expressing cortical thymocytes. Their semi-invariant alphabeta TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial alpha-glycuronylceramides found in the cell wall of Gram-negative, lipopolysaccharide-negative bacteria. This dual recognition of self and microbial ligands underlies innate-like antimicrobial functions mediated by CD40L induction and massive Th1 and Th2 cytokine and chemokine release. Through reciprocal activation of NKT cells and dendritic cells, synthetic NKT ligands constitute promising new vaccine adjuvants. NKT cells also regulate a range of immunopathological conditions, but the mechanisms and the ligands involved remain unknown. NKT cell biology has emerged as a new field of research at the frontier between innate and adaptive immunity, providing a powerful model to study fundamental aspects of the cell and structural biology of glycolipid trafficking, processing, and recognition. [Abstract]

Rabinovich GA, Gabrilovich D, Sotomayor EM
Immunosuppressive strategies that are mediated by tumor cells.
Annu Rev Immunol. 2007;25267-96.
Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression. [Abstract]

Williams MA, Bevan MJ
Effector and memory CTL differentiation.
Annu Rev Immunol. 2007;25171-92.
Technological advances in recent years have allowed for an ever-expanding ability to analyze and quantify in vivo immune responses. MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and "knockout" mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL). Understanding the mechanisms behind the differentiation of effector and memory CTL is of increasing importance to develop vaccination strategies against a variety of established and emerging infectious diseases. This review focuses on recent advances in our understanding of how effector and memory CTL differentiate and survive in vivo in response to viral or bacterial infection. [Abstract]

Leen AM, Rooney CM, Foster AE
Improving T cell therapy for cancer.
Annu Rev Immunol. 2007;25243-65.
Adoptive transfer of antigen-specific T lymphocytes is a powerful therapy for the treatment of opportunistic disease and some virus-associated malignancies such as Epstein-Barr virus-positive post-transplant lymphoproliferative disease. However, this strategy has been less successful in patients with nonviral cancers owing to their many and varied immune evasion mechanisms. These mechanisms include downregulation of target antigens and antigen-presenting machinery, secretion of inhibitory cytokines, and recruitment of regulatory immune cells to the tumor site. With increased understanding of the tumor microenvironment and the behavior and persistence of ex vivo-manipulated, adoptively transferred T cells, two novel approaches for increasing the efficacy of T cell therapy have been proposed. The first involves genetic modification of tumor-specific T cells to improve their biological function, for example by augmenting their ability to recognize tumor cells or their resistance to tumor-mediated immunosuppression. The second requires modifications to the host environment to improve the homeostatic expansion of infused T cells or to eliminate inhibitory T cell subsets. In this review, we discuss current, promising strategies to improve adoptive T cell therapy for the treatment of cancer. [Abstract]

Liu YJ, Soumelis V, Watanabe N, Ito T, Wang YH, Malefyt Rde W, Omori M, Zhou B, Ziegler SF
TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation.
Annu Rev Immunol. 2007;25193-219.
Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell-derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses. [Abstract]

Welniak LA, Blazar BR, Murphy WJ
Immunobiology of allogeneic hematopoietic stem cell transplantation.
Annu Rev Immunol. 2007;25139-70.
Allogeneic hematopoietic stem cell transplantation (HSCT) has evolved into an effective adoptive cellular immunotherapy for the treatment of a number of cancers. The immunobiology of allogeneic HSCT is unique in transplantation in that it involves potential immune recognition and attack between both donor and host. Much of the immunobiology of allogeneic HSCT has been gleaned from preclinical models and correlation with clinical observations. We review our current understanding of some of the issues that affect the success of this therapy, including host-versus-graft (HVG) reactions, graft-versus-host disease (GVHD), graft-versus-tumor (GVT) activity, and restoration of functional immunity to prevent transplant-related opportunistic infections. We also review new strategies to optimize the GVT and improve overall immune function while reducing GVHD and graft rejection. [Abstract]

Serhan CN
Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.
Annu Rev Immunol. 2007;25101-37.
Resolution of inflammation and the return of tissues to homeostasis are essential. Efforts to identify molecular events governing termination of self-limited inflammation uncovered pathways in resolving exudates that actively generate, from essential omega fatty acids, new families of local-acting mediators. These chemical mediator families, termed resolvins and protectins, are potent stereoselective agonists that control the duration and magnitude of inflammation, joining the lipoxins as signals in resolution. This review examines the mapping of these circuits and recent advances in our understanding of the biosynthesis and actions of these novel proresolving lipid mediators. Aspirin jump-starts resolution by triggering biosynthesis of specific epimers of these mediators. In addition to their origins in inflammation resolution, these compounds also display potent protective roles in neural systems, liver, lung, and eye. Given the potent actions of lipoxins, resolvins, and protectins in models of human disease, deficiencies in resolution pathways may contribute to many diseases and offer exciting new potential for therapeutic control via resolution. [Abstract]

Dustin LB, Rice CM
Flying under the radar: the immunobiology of hepatitis C.
Annu Rev Immunol. 2007;2571-99.
The hepatitis C virus (HCV) is a remarkably successful pathogen, establishing persistent infection in more than two-thirds of those who contract it. Its success is related to its abilities to blunt innate antiviral pathways and to evade adaptive immune responses. These two themes may be related. We propose that HCV takes advantage of the impaired innate response to delay the organization of an effective adaptive immune attack. The tolerogenic liver environment may provide cover, prolonging this delay. HCV's error-prone replication strategy permits rapid evolution under immune pressure. Persistent high levels of viral antigens may contribute to immune exhaustion. Finally, the virus may benefit from the efficient enlistment of memory T and B cells in the pursuit of a moving target. [Abstract]

Kollet O, Dar A, Lapidot T
The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization.
Annu Rev Immunol. 2007;2551-69.
Bone remodeling by bone-forming osteoblasts and bone-resorbing osteoclasts dynamically alters the bone inner wall and the endosteum region, which harbors osteoblastic niches for hematopoietic stem cells. Investigators have recently elucidated mechanisms of recruitment and mobilization; these mechanisms consist of stress signals that drive migration of leukocytes and progenitor cells from the bone marrow reservoir to the circulation and drive their homing to injured tissues as part of host defense and repair. The physical bone marrow vasculature barrier that is crossed by mobilized cells actively transmits chemotactic signals between the blood and the bone marrow, facilitating organ communication and cell trafficking. Osteoclasts play a dual role in regulation of bone resorption and homeostatic release or stress-induced mobilization of hematopoietic stem/progenitor cells. In this review, we discuss the orchestrated interplay between bone remodeling, the immune system, and the endosteal stem cell niches in the context of stem cell proliferation and migration during homeostasis, which are accelerated during alarm situations. [Abstract]

Recent Articles in Advances in Immunology

Nimmerjahn F, Ravetch JV
Fc-Receptors as Regulators of Immunity.
Adv Immunol. 2007;96C179-204.
Receptors for immunoglobulins [Fc-receptors (FcRs)] are widely expressed throughout the immune system. By binding to the antibody Fc-portion, they provide a link between the specificity of the adaptive immune system and the powerful effector functions triggered by innate immune effector cells. By virtue of coexpression of activating and inhibitory FcRs on the same cell, they set a threshold for immune cell activation by immune complexes (ICs). Besides their involvement in the efferent phase of an immune response, they are also important for modulating adaptive immune responses by regulating B cell and dendritic cell (DC) activation. Deletion of the inhibitory FcR leads to the loss of tolerance in the humoral immune system and the development of autoimmune disease. Uptake of ICs by FcRs on DCs and the concommitant triggering of activating and inhibitory signaling pathways will determine the strength of the initiated T-cell response. Loss of this balanced signaling results in uncontrolled responses that can lead to the damage of healthy tissues and ultimately to the initiation of autoimmune processes. In this chapter, we will discuss how coexpression of different activating and inhibitory receptors on different immune cells of the innate and adaptive immune system modulates cell activity. Moreover, we will focus on exogenous factors that can influence the balanced triggering of activating and inhibitory FcRs, such as the cytokine milieu and the role of differential antibody glycosylation. [Abstract]

Richards A, Kavanagh D, Atkinson JP
Inherited Complement Regulatory Protein Deficiency Predisposes to Human Disease in Acute Injury and Chronic Inflammatory StatesThe Examples of Vascular Damage in Atypical Hemolytic Uremic Syndrome and Debris Accumulation in Age-Related Macular Degeneration.
Adv Immunol. 2007;96141-77.
In this chapter, we examine the role of complement regulatory activity in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). These diseases are representative of two distinct types of complement-mediated injury, one being acute and self-limited, the other reflecting accumulation of chronic damage. Neither condition was previously thought to have a pathologic relationship to the immune system. However, alterations in complement regulatory protein genes have now been identified as major predisposing factors for the development of both diseases. In aHUS, heterozygous mutations leading to haploinsufficiency and function-altering polymorphisms in complement regulators have been identified, while in AMD, polymorphic haplotypes in complement genes are associated with development of disease. The basic premise is that a loss of function in a plasma or membrane inhibitor of the alternative complement pathway allows for excessive activation of complement on the endothelium of the kidney in aHUS and on retinal debris in AMD. These associations have much to teach us about the host's innate immune response to acute injury and to chronic debris deposition. We all experience cellular injury and, if we live long enough, will deposit debris in blood vessel walls (atherosclerosis leading to heart attacks and strokes), the brain (amyloid proteins leading to Alzheimer's disease), and retina (lipofuscin pigments leading to AMD). These are three common causes of morbidity and mortality in the developed world. The clinical, genetic, and immunopathologic understandings derived from the two examples of aHUS and AMD may illustrate what to anticipate in related conditions. They highlight how a powerful recognition and effector system, the alternative complement pathway, reacts to altered self. A response to acute injury or chronic debris accumulation must be appropriately balanced. In either case, too much activation or too little regulation promotes undesirable tissue damage and human disease. [Abstract]

Fearon DT
The expansion and maintenance of antigen-selected CD8(+) T cell clones.
Adv Immunol. 2007;96103-39.
The biological purpose of the mature, postthymic CD8(+) T cell is to respond to microbial antigens with a developmental program of clonal expansion and concomitant differentiation leading to effector cells (T(EFF)) that provide antimicrobial defense. Because many microbial infections persist into a chronic phase, this antigen-stimulated developmental program must be capable of continually generating T(EFF), perhaps for the lifetime of the individual. This chapter proposes that the ability of a CD8(+) T cell clone to maintain the continual production of T(EFF) during periods of persistent antigenic stimulation is based on a program that has two sequential phases of clonal expansion: an initial stage that occurs mainly in the secondary lymphoid tissues and is mediated by ligation of the T cell receptor (TCR) and CD27, and a subsequent, IL-2-dependent phase that occurs predominantly in peripheral, nonlymphoid tissues. The TCR/CD27-dependent phase establishes a nondifferentiating, self-renewing pool of clonally expanding cells, and the IL-2-dependent phase mediates continued clonal expansion that is coupled to the development of T(EFF). The two pools are linked by the process of asymmetrical division within the self-renewing subset so that, at steady state of cellular replication in this TCR/CD27-dependent subset, one daughter cell remains undifferentiated and the other initiates its commitment to IL-2-dependent terminal differentiation. Superimposed on this basic scheme are a shift in the CD8(+) T cell response to type I and II interferon (IFN) from anti- to pro-proliferative and transcriptional control of replicative senescence by Bmi-1, Blimp-1, and BCL6/BCL6b. This developmental program ensures that despite the occurrence of cellular senescence antiviral CD8(+) T cell clones are maintained for the duration of persistent viral infections. [Abstract]

Schoenborn JR, Wilson CB
Regulation of Interferon-gamma During Innate and Adaptive Immune Responses.
Adv Immunol. 2007;9641-101.
Interferon-gamma (IFN-gamma) is crucial for immunity against intracellular pathogens and for tumor control. However, aberrant IFN-gamma expression has been associated with a number of autoinflammatory and autoimmune diseases. This cytokine is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops. Herein, we briefly review the functions of IFN-gamma, the cells that produce it, the cell extrinsic signals that induce its production and influence the differentiation of naïve T cells into IFN-gamma-producing effector T cells, and the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine. We then review and discuss recent insights regarding the molecular regulation of IFN-gamma, focusing on work that has led to the identification and characterization of distal regulatory elements and epigenetic modifications with the IFN-gamma locus (Ifng) that govern its expression. The epigenetic modifications and three-dimensional structure of the Ifng locus in naive CD4 T cells, and the modifications they undergo as these cells differentiate into effector T cells, suggest a model whereby the chromatin architecture of Ifng is poised to facilitate either rapid opening or silencing during Th1 or Th2 differentiation, respectively. [Abstract]

Siffrin V, Brandt AU, Herz J, Zipp F
New insights into adaptive immunity in chronic neuroinflammation.
Adv Immunol. 2007;961-40.
Understanding the immune response in the central nervous system (CNS) is crucial for the development of new therapeutic concepts in chronic neuroinflammation, which differs considerably from other autoimmune diseases. Special immunologic properties of inflammatory processes in the CNS, which is often referred to as an immune privileged site, imply distinct features of CNS autoimmune disease in terms of disease initiation, perpetuation, and therapeutic accessibility. Furthermore, the CNS is a stress-sensitive organ with a low capacity for self-renewal and is highly prone to bystander damage caused by CNS inflammation. This leads to neuronal degeneration that contributes considerably to the phenotype of the disease. In this chapter, we discuss recent findings emphasizing the predominant role of the adaptive immune system in the pathogenesis of chronic neuroinflammation, that is, multiple sclerosis (MS) in patients and experimental autoimmune encephalomyelitis (EAE) in rodents. In addition, we report on efforts to translate these findings into clinical practice with the aim of developing selective treatment regimens. [Abstract]

Pejler G, Abrink M, Ringvall M, Wernersson S
Mast cell proteases.
Adv Immunol. 2007;95167-255.
Mast cells (MCs) are traditionally thought of as a nuisance for its host, for example, by causing many of the symptoms associated with allergic reactions. In addition, recent research has put focus on MCs for displaying harmful effects during various autoimmune disorders. On the other hand, MCs can also be beneficial for its host, for example, by contributing to the defense against insults such as bacteria, parasites, and snake venom toxins. When the MC is challenged by an external stimulus, it may respond by degranulation. In this process, a number of powerful preformed inflammatory "mediators" are released, including cytokines, histamine, serglycin proteoglycans, and several MC-specific proteases: chymases, tryptases, and carboxypeptidase A. Although the exact effector mechanism(s) by which MCs carry out their either beneficial or harmful effects in vivo are in large parts unknown, it is reasonable to assume that these mediators may contribute in profound ways. Among the various MC mediators, the exact biological function of the MC proteases has for a long time been relatively obscure. However, recent progress involving successful genetic targeting of several MC protease genes has generated powerful tools, which will enable us to unravel the role of the MC proteases both in normal physiology as well as in pathological settings. This chapter summarizes the current knowledge of the biology of the MC proteases. [Abstract]

David JP
Osteoimmunology: a view from the bone.
Adv Immunol. 2007;95149-65.
Osteoimmunology can be defined in a very broad sense as the field of research focusing on interrelations between bone and the immune system. This is a rather opened field that covers at least three different issues. The first one is developmental, that is, organogenesis of the bones and immune systems. The second is post-developmental, that is, the role of the bone in the regulation of the immune response and role of the immune cells on the regulation of bone homeostasis. The third one is related to pathologies: Can immune cells be involved in the development of bone-related pathology? Can deregulation of the bone be causing immune-related diseases? I will not review in detail the bibliography covering osteoimmunology. This has been extensively done in Immunological Reviews (Vol. 208, December 2005) and Current Opinion in Rheumatology (Vol. 18, 2006). I will rather critically comment on hypotheses and concepts in osteoimmunology from a bone biologist's point of view. [Abstract]

Hünig T
Manipulation of regulatory T-cell number and function with CD28-specific monoclonal antibodies.
Adv Immunol. 2007;95111-48.
Suppressor or "regulatory" CD4 T cells play a key role in the control of autoimmunity and overshooting immune responses to foreign antigens, but can also obstruct effective anticancer therapies. The homeostasis and activation of these regulatory T cells (Treg cells) is tightly connected to that of effector CD4 T cells via the costimulatory receptor CD28 and the cytokine IL-2: Both subsets require costimulation to be activated by antigen, and Treg cells additionally depend on IL-2 produced by effector CD4 T cells in a costimulation-dependent fashion. Depending on the therapeutic aim, blockade, or stimulation of CD28 with monoclonal antibodies (mAb) can therefore profoundly affect the size and activity of the Treg compartment. In this chapter, experiments performed in rodents with distinct types of CD28-specific mAb, and the recent failure to translate CD28-driven Treg activation into humans, are discussed. [Abstract]

Wardemann H, Nussenzweig MC
B-cell self-tolerance in humans.
Adv Immunol. 2007;9583-110.
Two mechanisms account for generation of the human antibody repertoire; V(D)J recombination during the early stages of B-cell development in the bone marrow and somatic mutation of immunoglobulin genes in mature B cells responding to antigen in the periphery. V(D)J recombination produces diversity by random joining of gene segments and somatic mutation by introducing random point mutations. Both are required to attain the degree of antigen receptor diversification that is necessary for immune protection: defects in either mechanism are associated with increased susceptibility to infection. However, the downside of producing enormous random diversity in the antibody repertoire is the generation of autoantibodies. To prevent autoimmunity B cells expressing autoantibodies are regulated by strict mechanisms that either modify the specificity of autoantibodies or the fate of cells expressing such antibodies. Abnormalities in B-cell self-tolerance are associated with a large number of autoimmune diseases, but the precise nature of the defects is less well defined. Here we summarize recent data on the self-reactive B-cell repertoire in healthy humans and in patients with autoimmunity. [Abstract]

Carneiro-Sampaio M, Coutinho A
Tolerance and autoimmunity: lessons at the bedside of primary immunodeficiencies.
Adv Immunol. 2007;9551-82.
The recent progress in the genetic characterization of many primary immunodeficiencies (PIDs) allows for a better understanding of immune molecular and cellular mechanisms. The present chapter discusses associations between PIDs and autoimmune diseases (AIDs) in this new light. PIDs are classified according to the frequency of association with AIDs, defining four groups of conditions: systematic (more than 80% of all patients), strong (10-80%), mild (less than 10%), and absent (no available descriptions). Several general conclusions could be drawn: (1) pathological autoimmune (AI) manifestations are very frequently associated with PIDs, indicating that, contrary to conventional notions, antimicrobial protection and natural tolerance to body tissues share many basic mechanisms; (2) in some gene defects, association is so strong that one could speak of "monogenic" AIDs; (3) basic types of PIDs are selectively associated with AID of a particular set of target tissues; (4) while for some gene defects, current theory satisfactorily explains pathogenesis of the corresponding AID, other situations suggest extensive gaps in the present understanding of natural tolerance; and (5) not exceptionally, observations on the AI phenotype for the same gene defect in mouse and man are not concordant, perhaps owing to the limited genetic diversity of mouse models, often limited to a single mouse strain. Overall, clinical observations on PID support the new paradigm of "dominant" tolerance to self-components, in which AID owes to deficits in immune responses (i.e., in regulatory mechanisms), rather than from excessive reactivity. [Abstract]

Monroe JG, Dorshkind K
Fate decisions regulating bone marrow and peripheral B lymphocyte development.
Adv Immunol. 2007;951-50.
In adult mammals, bone marrow pluripotent hematopoietic stem cells generate B lymphoid-specified progeny that progress through a series of well-characterized stages before generating B-cell receptor expressing B lymphocytes. These functionally immature B lymphocytes then migrate to the spleen wherein they differentiate through transitional stages into follicular or marginal zone B lymphocytes capable of responding to T-dependent and -independent antigens, respectively. During the terminal stages of B lymphocyte development in the bone marrow, as well as immediately following egress into the peripheral compartments, B lymphocytes are counterselected to eliminate B lymphocytes with potentially dangerous self-reactivity. These developmental and selection events in the bone marrow and periphery are dependent on the integration of intrinsic genetic programs with extrinsic microenvironmental signals that drive progenitors toward increasing B lineage commitment and maturation. This chapter provides a comprehensive overview of the various stages of primary and secondary B lymphocyte development with an emphasis on the selection processes that affect decisions at critical checkpoints. Our intent is to stress the concept that at many steps in the developmental process leading to a mature immunocompetent B lymphocyte, B lineage cells are integrating multiple and different signaling inputs that are translated into specific and appropriate cell fate decisions. [Abstract]

Durandy A, Taubenheim N, Peron S, Fischer A
Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies.
Adv Immunol. 2007;94275-306.
B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR) deficiencies, previously termed hyper-IgM syndromes, are genetically determined conditions characterized by normal or elevated serum IgM levels and an absence or very low levels of IgG, IgA, and IgE. As a function of the molecular mechanism, the defective CSR is variably associated to a defect in the generation of somatic hypermutations (SHMs) in the Ig variable region. The study of Ig-CSR deficiencies contributed to a better delineation of the mechanisms underlying CSR and SHM, the major events of antigen-triggered antibody maturation. Four Ig-CSR deficiency phenotypes have been so far reported: the description of the activation-induced cytidine deaminase (AID) deficiency (Ig-CSR deficiency 1), caused by recessive mutations of AICDA gene, characterized by a defect in CSR and SHM, clearly established the role of AID in the induction of the Ig gene rearrangements underlying CSR and SHM. A CSR-specific function of AID has, however, been detected by the observation of a selective CSR defect caused by mutations affecting the C-terminus of AID. Ig-CSR deficiency 2 is the consequence of uracil-N-glycosylase (UNG) deficiency. Because UNG, a molecule of the base excision repair machinery, removes uracils from DNA and AID deaminates cytosines into uracils, that observation indicates that the AID-UNG pathway directly targets DNA of switch regions from the Ig heavy-chain locus to induce the CSR process. Ig-CSR deficiencies 3 and 4 are characterized by a selective CSR defect resulting from blocks at distinct steps of CSR. A further understanding of the CSR machinery is expected from their molecular definition. [Abstract]

Okazaki IM, Kotani A, Honjo T
Role of AID in tumorigenesis.
Adv Immunol. 2007;94245-73.
A hallmark of mature B-cell lymphomas is reciprocal chromosomal translocations involving the Ig locus and a proto-oncogene, which usually result in the deregulated, constitutive expression of the translocated gene. In addition to such translocations, proto-oncogenes are frequently hypermutated in germinal center (GC)-derived B-cell lymphomas. Although aberrant, mistargeted class switch recombination (CSR) and somatic hypermutation (SHM) events have long been suspected of causing chromosomal translocations and mutations in oncogenes, and thus of playing a critical role in the pathogenesis of most B-cell lymphomas, the molecular basis for such deregulation of CSR and SHM is only beginning to be elucidated by recent genetic approaches. The tumorigenic ability of activation-induced cytidine deaminase (AID), a key enzyme that initiates CSR and SHM, was revealed in studies on AID transgenic mice. In addition, experiments with AID-deficient mice clearly showed that AID is required not only for the c-myc/IgH translocation but also for the malignant progression of translocation-bearing lymphoma precursor cells, probably by introducing additional genetic hits. Normally, AID expression is only transiently and specifically induced in activated B cells in GCs. However, recent studies indicate that AID can be induced directly in B cells outside the GCs by various pathogens, including transforming viruses associated with human malignancies. Indeed, AID expression is not restricted to GC-derived B-cell lymphomas, but is also found in other types of B-cell lymphoma and even in nonlymphoid tumors, suggesting that ectopically expressed AID is involved in tumorigenesis and disease progression in a wide variety of cell types. [Abstract]

Rosenberg BR, Papavasiliou FN
Beyond SHM and CSR: AID and related cytidine deaminases in the host response to viral infection.
Adv Immunol. 2007;94215-44.
As the primary effector of immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR), activation-induced cytidine deaminase (AID) serves an important function in the adaptive immune response. Recent advances have demonstrated that AID and a group of closely related cytidine deaminases, the APOBEC3 proteins, also act in the innate host response to viral infection. Antiviral activity was first attributed to APOBEC3G as a potent inhibitor of HIV. It is now apparent that the targets of the APOBEC3 proteins extend beyond HIV, with family members acting against a wide variety of viruses as well as host-encoded retrotransposable genetic elements. Although it appears to function through a different mechanism, AID also possesses antiviral properties. Independent of its antibody diversification functions, AID protects against transformation by Abelson murine leukemia virus (Ab-MLV), an oncogenic retrovirus. Additionally, AID has been implicated in the host response to other pathogenic viruses. These emerging roles for the AID/APOBEC cytidine deaminases in viral infection suggest an intriguing evolutionary connection of innate and adaptive immune mechanisms. [Abstract]

Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S, Perlot T, Vuong B, Wang J, Phan RT, Datta A, Manis J, Alt FW
Evolution of the immunoglobulin heavy chain class switch recombination mechanism.
Adv Immunol. 2007;94157-214.
To mount an optimum immune response, mature B lymphocytes can change the class of expressed antibody from IgM to IgG, IgA, or IgE through a recombination/deletion process termed immunoglobulin heavy chain (IgH) class switch recombination (CSR). CSR requires the activation-induced cytidine deaminase (AID), which has been shown to employ single-stranded DNA as a substrate in vitro. IgH CSR occurs within and requires large, repetitive sequences, termed S regions, which are parts of germ line transcription units (termed "C(H) genes") that are composed of promoters, S regions, and individual IgH constant region exons. CSR requires and is directed by germ line transcription of participating C(H) genes prior to CSR. AID deamination of cytidines in S regions appears to lead to S region double-stranded breaks (DSBs) required to initiate CSR. Joining of two broken S regions to complete CSR exploits the activities of general DNA DSB repair mechanisms. In this chapter, we discuss our current knowledge of the function of S regions, germ line transcription, AID, and DNA repair in CSR. We present a model for CSR in which transcription through S regions provides DNA substrates on which AID can generate DSB-inducing lesions. We also discuss how phosphorylation of AID may mediate interactions with cofactors that facilitate access to transcribed S regions during CSR and transcribed variable regions during the related process of somatic hypermutation (SHM). Finally, in the context of this CSR model, we further discuss current findings that suggest synapsis and joining of S region DSBs during CSR have evolved to exploit general mechanisms that function to join widely separated chromosomal DSBs. [Abstract]

Goodman MF, Scharff MD, Romesberg FE
AID-initiated purposeful mutations in immunoglobulin genes.
Adv Immunol. 2007;94127-55.
Exposure brings risk to all living organisms. Using a remarkably effective strategy, higher vertebrates mitigate risk by mounting a complex and sophisticated immune response to counter the potentially toxic invasion by a virtually limitless army of chemical and biological antagonists. Mutations are almost always deleterious, but in the case of antibody diversification there are mutations occurring at hugely elevated rates within the variable (V) and switch regions (SR) of the immunoglobulin (Ig) genes that are responsible for binding to and neutralizing foreign antigens throughout the body. These mutations are truly purposeful. This chapter is centered on activation-induced cytidine deaminase (AID). AID is required for initiating somatic hypermutation (SHM) in the V regions and class switch recombination (CSR) in the SR portions of Ig genes. By converting C --> U, while transcription takes place, AID instigates a cascade of mutational events involving error-prone DNA polymerases, base excision and mismatch repair enzymes, and recombination pathways. Together, these processes culminate in highly mutated antibody genes and the B cells expressing antibodies that have achieved optimal antigenic binding undergo positive selection in germinal centers. We will discuss the biological role of AID in this complex process, primarily in terms of its biochemical properties in relation to SHM in vivo. The chapter also discusses recent advances in experimental methods to characterize antibody dynamics as a function of SHM to help elucidate the role that the AID-induced mutations play in tailoring molecular recognition. The emerging experimental techniques help to address long-standing conundrums concerning evolution-imposed constraints on antibody structure and function. [Abstract]

Yang SY, Schatz DG
Targeting of AID-mediated sequence diversification by cis-acting determinants.
Adv Immunol. 2007;94109-25.
After their assembly by V(D)J recombination, immunoglobulin (Ig) genes undergo somatic hypermutation, gene conversion, and class switch recombination to generate additional antibody diversity. The three diversification processes depend on activation-induced cytidine deaminase (AID) and are tightly linked to transcription. The reactions occur primarily on Ig genes and the molecular mechanisms that underlie their targeting to Ig loci have been of intense interest. In this chapter, we discuss the evidence linking transcription and transcriptional control elements to the three diversification pathways, and we consider how various features of chromatin could render parts of the genome permissive for AID-mediated sequence diversification. [Abstract]

Ramiro A, San-Martin BR, McBride K, Jankovic M, Barreto V, Nussenzweig A, Nussenzweig MC
The role of activation-induced deaminase in antibody diversification and chromosome translocations.
Adv Immunol. 2007;9475-107.
Although B and T lymphocytes are similar in many respects including diversification of their antigen receptor genes by V(D)J recombination, 95% of all lymphomas diagnosed in the western world are of B-cell origin. Many of these are derived from mature B cells [Kuppers, R. (2005). Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 5, 251-262] and display hallmark chromosome translocations involving immunoglobulin genes and a proto-oncogene partner whose expression becomes deregulated as a result of the translocation reaction [Kuppers, R. (2005). Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 5, 251-262; Kuppers, R., and Dalla-Favera, R. (2001). Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580-5594]. These translocations are essential to the etiology of B-cell neoplasms. Here we will review how the B-cell specific molecular events required for immunoglobulin class switch recombination are initiated and how they contribute to chromosome translocations in vivo. [Abstract]

Conticello SG, Langlois MA, Yang Z, Neuberger MS
DNA deamination in immunity: AID in the context of its APOBEC relatives.
Adv Immunol. 2007;9437-73.
The activation-induced cytidine deaminase (AID)/apolipoprotein B RNA-editing catalytic component (APOBEC) family is a vertebrate-restricted subgrouping of a superfamily of zinc (Zn)-dependent deaminases that has members distributed throughout the biological world. AID and APOBEC2 are the oldest family members with APOBEC1 and the APOBEC3s being later arrivals restricted to placental mammals. Many AID/APOBEC family members exhibit cytidine deaminase activity on polynucleotides, although in different physiological contexts. Here, we examine the AID/APOBEC proteins in the context of the entire Zn-dependent deaminase superfamily. On the basis of secondary structure predictions, we propose that the cytosine and tRNA deaminases are likely to provide better structural paradigms for the AID/APOBEC family than do the cytidine deaminases, to which they have conventionally been compared. These comparisons yield predictions concerning likely polynucleotide-interacting residues in AID/APOBEC3s, predictions that are supported by mutagenesis studies. We also focus on a specific comparison between AID and the APOBEC3s. Both are DNA deaminases that function in immunity and are responsible for the hypermutation of their target substrates. AID functions in the adaptive immune system to diversify antibodies with targeted DNA deamination being central to this function. APOBEC3s function as part of an innate pathway of immunity to retroviruses with targeted DNA deamination being central to their activity in retroviral hypermutation. However, the mechanism by which the APOBEC3s fulfill their function of retroviral restriction remains unresolved. [Abstract]

Muramatsu M, Nagaoka H, Shinkura R, Begum NA, Honjo T
Discovery of activation-induced cytidine deaminase, the engraver of antibody memory.
Adv Immunol. 2007;941-36.
Discovery of activation-induced cytidine deaminase (AID) paved a new path to unite two genetic alterations induced by antigen stimulation; class switch recombination (CSR) and somatic hypermutation (SHM). AID is now established to cleave specific target DNA and to serve as engraver of these genetic alterations. AID of a 198-residue protein has four important domains: nuclear localization signal and SHM-specific region at the N-terminus; the alpha-helical segment (residue 47-54) responsible for dimerization; catalytic domain (residues 56-94) shared by all the other cytidine deaminase family members; and nuclear export signal overlapping with class switch-specific domain at the C-terminus. Two alternative models have been proposed for the mode of AID action; whether AID directly attacks DNA or indirectly through RNA editing. Lines of evidence supporting RNA editing hypothesis include homology in various aspects with APOBEC1, a bona fide RNA editing enzyme as well as requirement of de novo protein synthesis for DNA cleavage by AID in CSR and SHM. This chapter critically evaluates DNA deamination hypothesis and describes evidence to indicate UNG is involved not in DNA cleavage but in DNA repair of CSR. In addition, UNG appears to have a noncanonical function through interaction with an HIV Vpr-like protein at the WXXF motif. Taken together, RNA editing hypothesis is gaining the ground. [Abstract]

Hammad H, Lambrecht BN
Lung dendritic cell migration.
Adv Immunol. 2007;93265-78.
Dendritic cells (DCs) are crucial in regulating the immune response by bridging innate and adaptive immunity. DCs are constantly migrating from the blood to the lungs and from the lungs to the draining lymph nodes. How DCs populate the lung in the absence of inflammation and how they are recruited there during inflammation remain unclear. Since DCs play a central role in immune responses, both under steady-state and inflammatory conditions, detailed characterization of their migratory behavior may be essential for the development of future therapeutic strategies. [Abstract]

Minato N, Kometani K, Hattori M
Regulation of immune responses and hematopoiesis by the Rap1 signal.
Adv Immunol. 2007;93229-64.
Rap1 (Ras-proximity 1), a member of the Ras family of small guanine triphosphatases (GTPases), is activated by diverse extracellular stimuli. While Rap1 has been discovered originally as a potential Ras antagonist, accumulating evidence indicates that Rap1 per se mediates unique signals and exerts biological functions distinctly different from Ras. Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types. Recent studies (including gene-targeting analysis) have uncovered that the Rap1 signal is integrated crucially and unpredictably in the diverse aspects of comprehensive biological systems. This review summarizes the role of the Rap1 signal in developments and functions of the immune and hematopoietic systems as well as in malignancy. Importantly, Rap1 activation is tightly regulated in tissue cells, and dysregulations of the Rap1 signal in specific tissues result in certain disorders, including myeloproliferative disorders and leukemia, platelet dysfunction with defective hemostasis, leukocyte adhesion-deficiency syndrome, lupus-like systemic autoimmune disease, and T cell anergy. Many of these disorders resemble human diseases, and the Rap1 signal with its regulators may provide rational molecular targets for controlling certain human diseases including malignancy. [Abstract]

Kinashi T
Integrin regulation of lymphocyte trafficking: lessons from structural and signaling studies.
Adv Immunol. 2007;93185-227.
High trafficking capability of lymphocytes is crucial in immune surveillance and antigen responses. Central to this regulatory process is a dynamic control of lymphocyte adhesion behavior regulated by chemokines and adhesion receptors such as integrins. Modulation of lymphocyte adhesive responses occurs in a wide range of time window from less than a second to hours, enabling rolling lymphocyte to attach to and migrate through endothelium and interact with antigen-presenting cells. While there has been a rapid progress in the understanding of integrin structure, elucidation of signaling events to relay extracellular signaling to integrins in physiological contexts has recently emerged from studies using gene-targeting and gene-silencing technique. Regulatory molecules critical for integrin activity control distribution of integrins, polarized cell morphology and motility, suggesting a signaling network that coordinates integrin function with lymphocyte migration. Here, I review recent studies of integrin structural changes and intracellular signal molecules that trigger integrin activation (inside-out signals), and discuss molecular mechanisms that control lymphocyte integrins and how inside-out signals coordinately modulate adhesive reactions and cell shape and migration. [Abstract]

Felices M, Falk M, Kosaka Y, Berg LJ
Tec kinases in T cell and mast cell signaling.
Adv Immunol. 2007;93145-84.
The Tec family of tyrosine kinases consists of five members (Itk, Rlk, Tec, Btk, and Bmx) that are expressed predominantly in hematopoietic cells. The exceptions, Tec and Bmx, are also found in endothelial cells. Tec kinases constitute the second largest family of cytoplasmic protein tyrosine kinases. While B cells express Btk and Tec, and T cells express Itk, Rlk, and Tec, all four of these kinases (Btk, Itk, Rlk, and Tec) can be detected in mast cells. This chapter will focus on the biochemical and cell biological data that have been accumulated regarding Itk, Rlk, Btk, and Tec. In particular, distinctions between the different Tec kinase family members will be highlighted, with a goal of providing insight into the unique functions of each kinase. The known functions of Tec kinases in T cell and mast cell signaling will then be described, with a particular focus on T cell receptor and mast cell Fc epsilon RI signaling pathways. [Abstract]

Kikutani H, Suzuki K, Kumanogoh A
Immune semaphorins: increasing members and their diverse roles.
Adv Immunol. 2007;93121-43.
The semaphorin family consists of soluble and membrane-bound proteins originally identified as axonal guidance cues functioning during neuronal development. However, it is becoming increasingly clear that semaphorins play diverse roles in organogenesis, vascular growth, and tumor progression. In addition, emerging evidence indicates that several semaphorins, called "immune semaphorins," play crucial roles also during immune responses. Extensive studies on the immune semaphorins have revealed not only parallels but also differences in the semaphorin functions between the immune and nervous systems, providing unexpected but meaningful insights into the biological activities of these molecules. This chapter focuses on our current understanding of the roles of semaphorins and their receptors in the immune system. [Abstract]

Chang TW, Wu PC, Hsu CL, Hung AF
Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases.
Adv Immunol. 2007;9363-119.
The pharmacological purposes of the anti-IgE therapy are to neutralize IgE and to inhibit its production to attenuate type I hypersensitivity reactions. The therapy is based on humanized IgG1 antibodies that bind to free IgE and to membrane-bound IgE on B cells, but not to IgE bound by the high-affinity IgE.Fc receptors on basophils and mast cells or by the low-affinity IgE.Fc receptors on B cells. After nearly 20 years since inception, therapeutic anti-IgE antibodies (anti-IgE) have been studied in about 30 Phase II and III clinical trials in many allergy indications, and a lead antibody, omalizumab, has been approved for treating patients (12 years and older) with moderate-to-severe allergic asthma. Anti-IgE has confirmed the roles of IgE in the pathogenesis of asthma and helped define the concept "allergic asthma" in clinical practice. It has been shown to be safe and efficacious in treating pediatric allergic asthma and treating allergic rhinitis and is being investigated for treating peanut allergy, atopic dermatitis, latex allergy, and others. It has potential for use to combine with specific and rush immunotherapy for increased safety and efficacy. Anti-IgE thus appears to provide a prophylactic and therapeutic option for moderate to severe cases of many allergic diseases and conditions in which IgE plays a significant role. This chapter reviews the evolution of the anti-IgE concept and the clinical studies of anti-IgE on various disease indications, and presents a comprehensive analysis on the multiple intricate immunoregulatory pharmacological effects of anti-IgE. Finally, it reviews other approaches that target IgE or IgE-expressing B cells. [Abstract]

Pan-Hammarström Q, Zhao Y, Hammarström L
Class switch recombination: a comparison between mouse and human.
Adv Immunol. 2007;931-61.
Humans and mice separated more than 60 million years ago. Since then, evolution has led to a multitude of changes in their genomic sequences. The divergence of genes has resulted in differences both in the innate and adaptive immune systems. In this chapter, we focus on species difference with regard to immunoglobulin class switch recombination (CSR). We have compared the immunoglobulin constant region gene loci from human and mouse, with an emphasis on the switch regions, germ line transcription promoters, and 3' enhancers. We have also compared pathways/factors that are involved in CSR. Although there are remarkable similarities in the cellular machinery involved in CSR, there are also a number of unique features in each species. [Abstract]

Loureiro J, Ploegh HL
Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions.
Adv Immunol. 2006;92225-305.
Relatively small genomes and high replication rates allow viruses and bacteria to accumulate mutations. This continuously presents the host immune system with new challenges. On the other side of the trenches, an increasingly well-adjusted host immune response, shaped by coevolutionary history, makes a pathogen's life a rather complicated endeavor. It is, therefore, no surprise that pathogens either escape detection or modulate the host immune response, often by redirecting normal cellular pathways to their advantage. For the purpose of this chapter, we focus mainly on the manipulation of the class I and class II major histocompatibility complex (MHC) antigen presentation pathways and the ubiquitin (Ub)-proteasome system by both viral and bacterial pathogens. First, we describe the general features of antigen presentation pathways and the Ub-proteasome system and then address how they are manipulated by pathogens. We discuss the many human cytomegalovirus (HCMV)-encoded immunomodulatory genes that interfere with antigen presentation (immunoevasins) and focus on the HCMV immunoevasins US2 and US11, which induce the degradation of class I MHC heavy chains by the proteasome by catalyzing their export from the endoplasmic reticulum (ER)-membrane into the cytosol, a process termed ER dislocation. US2- and US11-mediated subversion of ER dislocation ensures proteasomal degradation of class I MHC molecules and presumably allows HCMV to avoid recognition by cytotoxic T cells, whilst providing insight into general aspects of ER-associated degradation (ERAD) which is used by eukaryotic cells to purge their ER of defective proteins. We discuss the similarities and differences between the distinct pathways co-opted by US2 and US11 for dislocation and degradation of human class I MHC molecules and also a putatively distinct pathway utilized by the murine herpes virus (MHV)-68 mK3 immunoevasin for ER dislocation of murine class I MHC. We speculate on the implications of the three pathogen-exploited dislocation pathways to cellular ER quality control. Moreover, we discuss the ubiquitin (Ub)-proteasome system and its position at the core of antigen presentation as proteolysis and intracellular trafficking rely heavily on Ub-dependent processes. We add a few examples of manipulation of the Ub-proteasome system by pathogens in the context of the immune system and such diverse aspects of the host-pathogen relationship as virus budding, bacterial chromosome integration, and programmed cell death, to name a few. Finally, we speculate on newly found pathogen-encoded deubiquitinating enzymes (DUBs) and their putative roles in modulation of host-pathogen interactions. [Abstract]

Romero P, Cerottini JC, Speiser DE
The human T cell response to melanoma antigens.
Adv Immunol. 2006;92187-224.
The cornerstone of the concept of immunosurveillance in cancer should be the experimental demonstration of immune responses able to alter the course of in vivo spontaneous tumor progression. Elegant genetic manipulation of the mouse immune system has proved this tenet. In parallel, progress in understanding human T cell mediated immunity has allowed to document the existence in cancer patients of naturally acquired T cell responses to molecularly defined tumor antigens. Various attributes of cutaneous melanoma tumors, notably their adaptability to in vitro tissue culture conditions, have contributed to convert this tumor in the prototype for studies of human antitumor immune responses. As a consequence, the first human cytolytic T lymphocyte (CTL)-defined tumor antigen and numerous others have been identified using lymphocyte material from patients bearing this tumor, detailed analyses of specific T cell responses have been reported and a relatively large number of clinical trials of vaccination have been performed in the last 15 years. Thus, the "melanoma model" continues to provide valuable insights to guide the development of clinically effective cancer therapies based on the recruitment of the immune system. This chapter reviews recent knowledge on human CD8 and CD4 T cell responses to melanoma antigens. [Abstract]

Gavrieli M, Sedy J, Nelson CA, Murphy KM
BTLA and HVEM cross talk regulates inhibition and costimulation.
Adv Immunol. 2006;92157-85.
Recently a new inhibitory immunoglobulin domain-containing lymphocyte receptor was identified on the basis of its T helper 1 (T(H)1)-selective expression in murine T cell lines, which was named B and T lymphocyte attenuator (BTLA). Several groups have confirmed the initial characterization of BTLA as an inhibitory receptor, which was initially inferred from the mild increases in several parameters of BTLA-deficient mice. The initial expectation that BTLA would interact with a B7 family ligand, such as the B7x protein, was surprisingly overturned with the functional cloning of the actual BTLA ligand as herpesvirus entry mediator (HVEM). This was unexpected largely due to the fact that this interaction represents the convergence of two very different, although each quite extensive, families of receptors and ligands. The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is quite unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and which are the signaling events downstream of receptor ligation. As we discuss here and recently demonstrated, HVEM interaction with BTLA serves to negatively regulate T cell responses, in contrast to the strong activation observed when HVEM engages its endogenous ligand from the TNF family. Finally, as studies of BTLA are just now beginning to extend beyond the initial characterizations, it is becoming clear that there are many complex issues remaining to be resolved, particularly potential polymorphisms that may engender disease susceptibility in the human. [Abstract]

Recent Articles in Immunity

Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, Das PP, Miska EA, Rodriguez A, Bradley A, Smith KG, Rada C, Enright AJ, Toellner KM, Maclennan IC, Turner M
microRNA-155 Regulates the Generation of Immunoglobulin Class-Switched Plasma Cells.
Immunity. 2007 Dec 3;
microRNA-155 (miR-155) is expressed by cells of the immune system after activation and has been shown to be required for antibody production after vaccination with attenuated Salmonella. Here we show the intrinsic requirement for miR-155 in B cell responses to thymus-dependent and -independent antigens. B cells lacking miR-155 generated reduced extrafollicular and germinal center responses and failed to produce high-affinity IgG1 antibodies. Gene-expression profiling of activated B cells indicated that miR-155 regulates an array of genes with diverse function, many of which are predicted targets of miR-155. The transcription factor Pu.1 is validated as a direct target of miR155-mediated inhibition. When Pu.1 is overexpressed in wild-type B cells, fewer IgG1 cells are produced, indicating that loss of Pu.1 regulation is a contributing factor to the miR-155-deficient phenotype. Our results implicate post-transcriptional regulation of gene expression for establishing the terminal differentiation program of B cells. [Abstract]

Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Böll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A
Human Leukocyte Antigen-B-Associated Transcript 3 Is Released from Tumor Cells and Engages the NKp30 Receptor on Natural Killer Cells.
Immunity. 2007 Dec 3;
The activity of natural killer (NK) cells is regulated by surface receptors, which direct target cell recognition. NKp30 (Natural Cytotoxicity Receptor 3) induces target cell lysis and is also crucial for the interaction with dendritic cells. So far, the cellular ligands for NKp30 have remained elusive. Here we show that the nuclear factor HLA-B-associated transcript 3 (BAT3) was released from tumor cells, bound directly to NKp30, and engaged NKp30 on NK cells. BAT3 triggered NKp30-mediated cytotoxicity and was necessary for tumor rejection in a multiple myeloma model. These data identify BAT3 as a cellular ligand for NKp30. We propose a concept for target cell recognition by NK cells beyond "missing self" and "induced self," mediated through a tumor cell-derived extracellular factor. [Abstract]

Le Y, Zhu BM, Harley B, Park SY, Kobayashi T, Manis JP, Luo HR, Yoshimura A, Hennighausen L, Silberstein LE
SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis.
Immunity. 2007 Nov;27(5):811-23.
The chemokine CXCL12 induces prolonged focal adhesion kinase (FAK) phosphorylation and sustained proadhesive responses in progenitor bone-marrow (BM) B cells, but not in mature peripheral B cells. Here we demonstrate that suppressor of cytokine signaling 3 (SOCS3) regulated CXCL12-induced FAK phosphorylation through the ubiquitin-proteasome pathway. CXCL12 triggered increased FAK ubiquitination in mature B cells, but not in progenitor B cells. Accordingly, SOCS3 expression was low in progenitor B cells, increased in immature B cells, and highest in mature B cells. SOCS3 overexpression in pro-B cells impaired CXCL12-induced FAK phosphorylation and proadhesive responses. Conversely, SOCS3-deficient mature B cells from Cre(MMTV)Socs3(fl/fl) mice exhibited prolonged FAK phosphorylation and adhesion to VCAM-1. In contrast to wild-type mice, Cre(MMTV)Socs3(fl/fl) mice had a 2-fold increase in immature B cells, which were evenly distributed in endosteal and perisinusoidal BM compartments. We propose that the developmental regulation of CXCR4-FAK signaling by SOCS3 is an important mechanism to control the lodgement of B cell precursors in the BM microenvironment. [Abstract]

Horai R, Mueller KL, Handon RA, Cannons JL, Anderson SM, Kirby MR, Schwartzberg PL
Requirements for selection of conventional and innate T lymphocyte lineages.
Immunity. 2007 Nov;27(5):775-85.
Mice deficient in the Tec kinase Itk develop a large population of CD8(+) T cells with properties, including expression of memory markers, rapid production of cytokines, and dependence on Interleukin-15, resembling NKT and other innate T cell lineages. Like NKT cells, these CD8(+) T cells can be selected on hematopoietic cells. We demonstrate that these CD8(+) T cell phenotypes resulted from selection on hematopoietic cells-forcing selection on the thymic stroma reduced the number and innate phenotypes of mature Itk-deficient CD8(+) T cells. We further show that, similar to NKT cells, selection of innate-type CD8(+) T cells in Itk(-/-) mice required the adaptor SAP. Acquisition of their innate characteristics, however, required CD28. Our results suggest that SAP and Itk reciprocally regulate selection of innate and conventional CD8(+) T cells on hematopoietic cells and thymic epithelium, respectively, whereas CD28 regulates development of innate phenotypes resulting from selection on hematopoietic cells. [Abstract]

Li W, Sofi MH, Rietdijk S, Wang N, Terhorst C, Chang CH
The SLAM-Associated Protein Signaling Pathway Is Required for Development of CD4(+) T Cells Selected by Homotypic Thymocyte Interaction.
Immunity. 2007 Nov;27(5):763-74.
MHC class II-expressing double-positive thymocytes induce progression of CD4(+) T cell development as efficiently as cortical thymic epithelial cells do. Because double-positive thymocytes expressing CD1d select natural killer T (NKT) cells, we investigated whether thymocyte-selected CD4(+) (T-CD4) T cells require the same signaling components as NKT cells. Using bone-marrow chimeras, we found that the signaling molecules SAP, Fyn, and PKCtheta were essential for T-CD4 T cell generation, whereas mutations in the Ly108 receptor, interleukin-15 receptor alpha, or the transcription factor T-bet had a marginal effect. Furthermore, SAP was critical for IL-4 production by T-CD4 T cells, but the PKCtheta deficiency did not alter the ability of T-CD4 T cells to produce cytokines. T-bet was necessary to produce the maximum amount of IFN-gamma for CD4(+) T cells regardless of the selection pathway. Thus, in contrast to epithelial cell-selected CD4(+) T cells, the two distinct lineages of T cells selected by thymocytes-i.e., T-CD4 and NKT cells-both utilize the SAP-Fyn-PKCtheta pathway for their development and function. [Abstract]

Griewank K, Borowski C, Rietdijk S, Wang N, Julien A, Wei DG, Mamchak AA, Terhorst C, Bendelac A
Homotypic interactions mediated by slamf1 and slamf6 receptors control NKT cell lineage development.
Immunity. 2007 Nov;27(5):751-62.
Commitment to the T and natural killer T (NKT) cell lineages is determined during alphabeta T cell receptor (TCR)-mediated interactions of common precursors with ligand-expressing cells in the thymus. Whereas mainstream thymocyte precursors recognize major histocompatibility complex (MHC) ligands expressed by stromal cells, NKT cell precursors interact with CD1d ligands expressed by cortical thymocytes. Here, we demonstrated that such homotypic T-T interactions generated "second signals" mediated by the cooperative engagement of the homophilic receptors Slamf1 (SLAM) and Slamf6 (Ly108) and the downstream recruitment of the adaptor SLAM-associated protein (SAP) and the Src kinase Fyn, which are essential for the lineage expansion and differentiation of the NKT cell lineage. These receptor interactions were required during TCR engagement and therefore only occurred when selecting ligands were presented by thymocytes rather than epithelial cells, which do not express Slamf6 or Slamf1. Thus, the topography of NKT cell ligand recognition determines the availability of a cosignaling pathway that is essential for NKT cell lineage development. [Abstract]

Veillette A, Dong Z, Latour S
Consequence of the SLAM-SAP Signaling Pathway in Innate-like and Conventional Lymphocytes.
Immunity. 2007 Nov 26;27(5):698-710.
Signaling lymphocytic activation molecule (SLAM) family receptors mediate important regulatory signals in immune cells, as a result of their exquisite ability to associate with members of the SLAM-associated protein (SAP) family of adaptors. As discussed herein, recent findings show that the SLAM and SAP families carry out pivotal functions in innate-like and conventional lymphocytes. They are critically needed for the development of innate-like lymphocytes such as NKT cells. In addition, they influence several of the functions of conventional lymphocytes, including the ability of CD4(+) T cells to secrete certain cytokines and mediate B cell help; CD8(+) T cell proliferation and cytokine production; NK cell-mediated cytotoxicity; and B cell antibody production. These unique functional properties appear to be facilitated by the ability of SLAM-related receptors to serve as self-ligands during homotypic interactions between immune cells. The importance of the SLAM-SAP pathway in normal immunity is highlighted by the finding that SAP is mutated in humans suffering from the immunodeficiency X-linked lymphoproliferative disease. [Abstract]

Krieg AM
The Toll of Too Much TLR7.
Immunity. 2007 Nov;27(5):695-7.
Toll-like receptor 7 (TLR7) detects viral RNA, but can be activated inappropriately by self-RNA, leading to autoimmunity. Deane et al. (2007) show that Tlr7 gene dosage is directly related to the risk of lupus in a mouse model. [Abstract]

Chatila T
The regulatory T cell transcriptosome: e pluribus unum.
Immunity. 2007 Nov;27(5):693-5.
The regulatory T (Treg) cell transcriptional program is formed of distinct genetic networks that respond to different activators. In this issue of Immunity, Hill et al. (2007) provide insights into the interactions among the different networks and the overall role of Foxp3 in shaping the Treg cell transcriptosome. [Abstract]

Kappes DJ
CD4 and CD8: Hogging All the Lck.
Immunity. 2007 Nov;27(5):691-3.
Specificity of T cell receptors (TCRs) to major histocompatibility complex (MHC) might be intrinsic or imposed by thymic selection. Van Laethem et al. (2007) propose that the sequestration of the kinase Lck by coreceptors prevents the selection of non-MHC-reactive TCRs. [Abstract]

McKee AS, Munks MW, Marrack P
How do adjuvants work? Important considerations for new generation adjuvants.
Immunity. 2007 Nov;27(5):687-90.
In this Commentary, McKee et al. highlight the properties of extrinsic vaccine adjuvants that must be considered to achieve the most protective immune response, as occurs naturally with many intrinsic pathogen-derived adjuvants. [Abstract]

Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C
Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature.
Immunity. 2007 Nov;27(5):786-800.
The CD4(+)CD25(+) lineage of regulatory T (Treg) cells plays a key role in controlling immune and autoimmune responses and is characterized by a unique transcriptional signature. The transcription factor Foxp3 had been thought to determine the Treg cell lineage, a hypothesis challenged by recent observations. We have performed a cross-sectional analysis of the Treg cell signature in Treg-like cells generated under a number of conditions, with or without Foxp3, to delineate the elements that can be ascribed to T cell activation, interleukin-2, transforming growth factor-beta (TGF-beta) signaling, or Foxp3 itself. These influences synergized to determine many of the signature's components. Much of the Treg cell signature was not ascribable to Foxp3 because it contained gene clusters that are coregulated with, but not transactivated by, Foxp3. Thus, a higher level of regulation upstream of Foxp3 determines the lineage, distinct from elements downstream of Foxp3 that are essential for its regulatory properties. [Abstract]

Van Laethem F, Sarafova SD, Park JH, Tai X, Pobezinsky L, Guinter TI, Adoro S, Adams A, Sharrow SO, Feigenbaum L, Singer A
Deletion of CD4 and CD8 Coreceptors Permits Generation of alphabetaT Cells that Recognize Antigens Independently of the MHC.
Immunity. 2007 Nov;27(5):735-50.
The thymus generates major histocompatibility complex (MHC)-restricted alphabetaT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that MHC specificity might be imposed on a broader alphabetaTCR repertoire during thymic selection by CD4 and CD8 coreceptors that bind and effectively sequester the tyrosine kinase Lck, thereby preventing T cell receptor (TCR) signaling by non-MHC ligands that do not engage either coreceptor. This hypothesis predicts that, in coreceptor-deficient mice, alphabeta thymocytes would be signaled by non-MHC ligands to differentiate into alphabetaT cells lacking MHC specificity. We now report that MHC-independent alphabetaT cells were indeed generated in mice deficient in both coreceptors as well as MHC ("quad-deficient" mice) and that such mice contained a diverse alphabetaT cell repertoire whose MHC independence was confirmed at the clonal level. We conclude that CD4 and CD8 coreceptors impose MHC specificity on a broader alphabetaTCR repertoire during thymic selection by preventing thymocytes from being signaled by non-MHC ligands. [Abstract]

Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, Flavell RA, Bolland S
Control of Toll-like Receptor 7 Expression Is Essential to Restrict Autoimmunity and Dendritic Cell Proliferation.
Immunity. 2007 Nov;27(5):801-10.
Nucleic acid-binding innate immune receptors such as Toll-like receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa, which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses. [Abstract]

Wuerffel R, Wang L, Grigera F, Manis J, Selsing E, Perlot T, Alt FW, Cogne M, Pinaud E, Kenter AL
S-S Synapsis during Class Switch Recombination Is Promoted by Distantly Located Transcriptional Elements and Activation-Induced Deaminase.
Immunity. 2007 Nov;27(5):711-22.
Molecular mechanisms underlying synapsis of activation-induced deaminase (AID)-targeted S regions during class switch recombination (CSR) are poorly understood. By using chromosome conformation capture techniques, we found that in B cells, the Emu and 3'Ealpha enhancers were in close spatial proximity, forming a unique chromosomal loop configuration. B cell activation led to recruitment of the germline transcript (GLT) promoters to the Emu:3'Ealpha complex in a cytokine-dependent fashion. This structure facilitated S-S synapsis because Smu was proximal to Emu and a downstream S region was corecruited with the targeted GLT promoter to Emu:3'Ealpha. We propose that GLT promoter association with the Emu:3'Ealpha complex creates an architectural scaffolding that promotes S-S synapsis during CSR and that these interactions are stabilized by AID. Thus, the S-S synaptosome is formed as a result of the self-organizing transcription system that regulates GLT expression and may serve to guard against spurious chromosomal translocations. [Abstract]

Naito T, Gómez-Del Arco P, Williams CJ, Georgopoulos K
Antagonistic Interactions between Ikaros and the Chromatin Remodeler Mi-2beta Determine Silencer Activity and Cd4 Gene Expression.
Immunity. 2007 Nov;27(5):723-34.
Lineage commitment is induced by changes in gene expression dictated by the intimate interaction between transcription factors and chromatin regulators. Here, we revealed the antagonistic interplay between Ikaros and its associate the chromatin remodeler Mi-2beta during T cell development, as exemplified by the regulation of Cd4 expression. Loss of Ikaros or Mi-2beta led to activation or repression, respectively, of the Cd4 locus at inappropriate stages of development. Their combined mutation reverted to normal CD4 expression. In double-negative thymocytes, Ikaros binding to the Cd4 silencer contributed to its repressive activity. In double-positive thymocytes, concomitant binding of Mi-2beta with Ikaros to the Cd4 silencer caused silencer inactivation, thereby allowing for CD4 expression. Mi-2beta facilitated recruitment of histone acetyl transferases to the silencer. This recruitment possibly antagonized Ikaros and associated repressive activities. Thus, concomitant interactions between functionally opposing chromatin-regulating machineries are an important mode of gene regulation during lineage determination. [Abstract]

Kanneganti TD, Lamkanfi M, Núñez G
Intracellular NOD-like receptors in host defense and disease.
Immunity. 2007 Oct;27(4):549-59.
The innate immune system comprises several classes of pattern recognition receptors, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-1-like receptors (RLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs and RLRs detect microbial components in the cytosol. Here we discuss the recent understanding in NLRs. Two NLRs, NOD1 and NOD2, sense the cytosolic presence of the peptidoglycan fragments meso-DAP and muramyl dipeptide, respectively, and drive the activation of mitogen-activated protein kinase (MAPK) and the transcription factor NF-kappaB. A different set of NLRs induces caspase-1 activation through the assembly of large protein complexes named inflammasomes. Genetic variations in several NLR members are associated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defense and the pathogenesis of inflammatory diseases. [Abstract]

Stetson DB, Medzhitov R
T helper 17 cells get the NOD.
Immunity. 2007 Oct;27(4):546-8.
Interleukin-17 (IL-17)-producing helper T cells play a role in pathogen defense and autoimmunity. In this issue of Immunity, van Beelen et al. (2007) reveal a pathway that elicits potent IL-17 production from memory T cells through activation of the intracellular receptor NOD2. [Abstract]

van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC
Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells.
Immunity. 2007 Oct;27(4):660-9.
How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells. The role of NOD2 in this IL-23-IL-1-IL-17 axis could be confirmed in NOD2-deficient DCs, such as DCs from selected Crohn's disease patients. Thus, antibacterial Th17-mediated immunity in humans is orchestrated by DCs upon sensing bacterial NOD2-ligand MDP. [Abstract]

van den Broek M
Dendritic cells break bonds to tolerize.
Immunity. 2007 Oct;27(4):544-6.
Typically, dendritic cells (DCs) induce peripheral tolerance under steady state but immunity during inflammation or infection. In this issue of Immunity, Jiang et al. (2007) identify disruption of E-cadherin interactions as a unique maturation pathway by which DCs are capable of mediating tolerance. [Abstract]

Jiang A, Bloom O, Ono S, Cui W, Unternaehrer J, Jiang S, Whitney JA, Connolly J, Banchereau J, Mellman I
Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation.
Immunity. 2007 Oct;27(4):610-24.
The maturation of dendritic cells (DCs) after exposure to microbial products or inflammatory mediators plays a critical role in initiating the immune response. We found that maturation can also occur under steady-state conditions, triggered by alterations in E-cadherin-mediated DC-DC adhesion. Selective disruption of these interactions induced the typical features of DC maturation including the upregulation of costimulatory molecules, MHC class II, and chemokine receptors. These events were triggered at least in part by activation of the beta-catenin pathway. However, unlike maturation induced by microbial products, E-cadherin-stimulated DCs failed to release immunostimulatory cytokines, exhibiting an entirely different transcriptional profile. As a result, E-cadherin-stimulated DCs elicited an entirely different T cell response in vivo, generating T cells with a regulatory as opposed to an effector phenotype. These DCs induced tolerance in vivo and may thus contribute to the elusive steady-state "tolerogenic DCs." [Abstract]

Ferrandon D
Ubiquitin-proteasome: pallbearer carries the deceased to the grave.
Immunity. 2007 Oct;27(4):541-4.
Phagocytosis is a complex process that involves multiple cellular functions. In this issue of Immunity, Silva et al. (2007) report that a protein ubiquitylation complex and the proteasome are required for the clearance of apoptotic cells in Drosophila. [Abstract]

Silva E, Au-Yeung HW, Van Goethem E, Burden J, Franc NC
Requirement for a Drosophila E3-ubiquitin ligase in phagocytosis of apoptotic cells.
Immunity. 2007 Oct;27(4):585-96.
Many cells die by apoptosis during animal development. Apoptotic cells are rapidly removed through phagocytosis by their neighbors or by macrophages. To genetically dissect this process, we performed an in vivo screen for genes required for efficient phagocytosis of apoptotic cells by Drosophila macrophages and identified pallbearer (pall), which encodes an F box protein. F box proteins generally provide substrate specificity to Skp Cullin F box (SCF) complexes, acting as E3 ligases that target phosphorylated proteins to ubiquitylation and degradation via the 26S proteasome. We showed that Pallbearer functions in an SCF-dependent manner and provided direct evidence of a role for ubiquitylation and proteasomal degradation in phagocytosis of apoptotic corpses in vivo. This work might further our understanding of the regulation of apoptotic cell engulfment and thus our understanding of innate immunity as a whole. [Abstract]

Oltz EM, Osipovich O
Targeting V(D)J recombinase: putting a PHD to work.
Immunity. 2007 Oct;27(4):539-41.
In this issue of Immunity, Liu et al. (2007) show that V(D)J recombinase binds chromatin marked by H3K4 trimethylation. Because this mark associates with active promoters, the finding forges a new link between transcription, epigenetics, and recombinase targeting during lymphocyte development. [Abstract]

Liu Y, Subrahmanyam R, Chakraborty T, Sen R, Desiderio S
A plant homeodomain in RAG-2 that binds Hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement.
Immunity. 2007 Oct;27(4):561-71.
V(D)J recombination is initiated by the recombination activating gene (RAG) proteins RAG-1 and RAG-2. The ability of antigen-receptor-gene segments to undergo V(D)J recombination is correlated with spatially- and temporally-restricted chromatin modifications. We have found that RAG-2 bound specifically to histone H3 and that this binding was absolutely dependent on dimethylation or trimethylation at lysine 4 (H3K4me2 or H3K4me3). The interaction required a noncanonical plant homeodomain (PHD) that had previously been described within the noncore region of RAG-2. Binding of the RAG-2 PHD finger to chromatin across the IgH D-J(H)-C locus showed a strong correlation with the distribution of trimethylated histone H3 K4. Mutation of a conserved tryptophan residue in the RAG-2 PHD finger abolished binding to H3K4me3 and greatly impaired recombination of extrachromosomal and endogenous immunoglobulin gene segments. Together, these findings are consistent with the interpretation that recognition of hypermethylated histone H3 K4 promotes efficient V(D)J recombination in vivo. [Abstract]

Gross S, Moss BL, Piwnica-Worms D
Veni, vidi, vici: in vivo molecular imaging of immune response.
Immunity. 2007 Oct;27(4):533-8.
"I came, I saw, I conquered," Julius Caesar proclaimed, highlighting the importance of direct visualization as a winning strategy. Continuing the "From the Field" series (see Editorial [2007] 26, 131), Gross et al. summarize how modern molecular imaging techniques can successfully dissect the complexities of immune response in vivo. [Abstract]

Velikovsky CA, Deng L, Chlewicki LK, Fernández MM, Kumar V, Mariuzza RA
Structure of natural killer receptor 2B4 bound to CD48 reveals basis for heterophilic recognition in signaling lymphocyte activation molecule family.
Immunity. 2007 Oct;27(4):572-84.
Natural killer (NK) cells eliminate virally infected and tumor cells. Among the receptors regulating NK cell function is 2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM) family that binds CD48. 2B4 is the only heterophilic receptor of the SLAM family, whose other members, e.g., NK-T-B-antigen (NTB-A), are self-ligands. We determined the structure of the complex between the N-terminal domains of mouse 2B4 and CD48, as well as the structures of unbound 2B4 and CD48. The complex displayed an association mode related to, yet distinct from, that of the NTB-A dimer. Binding was accompanied by the rigidification of flexible 2B4 regions containing most of the polymorphic residues across different species and receptor isoforms. We propose a model for 2B4-CD48 interactions that permits the intermixing of SLAM receptors with major histocompatibility complex-specific receptors in the NK cell immune synapse. This analysis revealed the basis for heterophilic recognition within the SLAM family. [Abstract]

Paget C, Mallevaey T, Speak AO, Torres D, Fontaine J, Sheehan KC, Capron M, Ryffel B, Faveeuw C, Leite de Moraes M, Platt F, Trottein F
Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids.
Immunity. 2007 Oct;27(4):597-609.
Invariant natural killer T (iNKT) cells are a subset of innate lymphocytes that recognize lipid antigens in the context of CD1d and mediate potent immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). We investigated whether diverse Toll-like receptor (TLR) signals in myeloid dendritic cells (DCs) could differentially stimulate iNKT cells. Together with the lipopolysaccharide-detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-gamma, but not IL-4. iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged beta-linked glycosphingolipid(s) by DCs. In addition, DCs stimulated via TLR9 activated both iNKT cells and NK cells in vivo and protected mice against B16F10-induced melanoma metastases. These data underline the role of TLR9 in iNKT cell activation and might have relevance to infectious diseases and cancer. [Abstract]

Celli S, Lemaître F, Bousso P
Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation.
Immunity. 2007 Oct;27(4):625-34.
T cells interact with dendritic cells (DCs) for periods lasting from minutes to hours. However, a causal link between the duration of this interaction and the efficiency of T cell activation has not been established in vivo. Employing intravital two-photon imaging, we manipulated T cell-DC interactions in real time and found that the first T cell-DC encounter often resulted in a long-lived interaction. Moreover, the cessation of T cell receptor-major histocompatibility complex signals promoted cellular dissociation, suggesting that antigen availability on DCs regulates contact duration. Finally, at least 6 hr of in vivo T cell-DC interaction were required for naive CD4(+) T cells to undergo clonal expansion. These results establish the importance of prolonged T cell-DC interactions for efficient CD4(+) T cell activation in vivo. [Abstract]

Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R
Molecular signature of CD8+ T cell exhaustion during chronic viral infection.
Immunity. 2007 Oct;27(4):670-84.
Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cells from chronic infection to functional LCMV-specific effector and memory CD8(+) T cells generated after acute infection. These data showed that exhausted CD8(+) T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections. [Abstract]

Recent Articles in Nature Immunology

Goto A, Matsushita K, Gesellchen V, Chamy LE, Kuttenkeuler D, Takeuchi O, Hoffmann JA, Akira S, Boutros M, Reichhart JM
Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice.
Nat Immunol. 2007 Dec 9;
During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses. [Abstract]

Ramalingam TR, Pesce JT, Sheikh F, Cheever AW, Mentink-Kane MM, Wilson MS, Stevens S, Valenzuela DM, Murphy AJ, Yancopoulos GD, Urban JF, Donnelly RP, Wynn TA
Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain.
Nat Immunol. 2007 Dec 9;
The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (T(H)2)-mediated disease and associates with either the common gamma-chain to form the type I IL-4R or with the IL-13R alpha1 chain (IL-13Ralpha1) to form the type II IL-4R. Here we used Il13ra1(-/-) mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra(-/-) mice, which have weak T(H)2 responses, Il13ra1(-/-) mice had exacerbated T(H)2 responses. Il13ra1(-/-) mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Ralpha1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses. [Abstract]

Kano SI, Sato K, Morishita Y, Vollstedt S, Kim S, Bishop K, Honda K, Kubo M, Taniguchi T
The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and T(H)1 versus T(H)-17 differentiation of CD4(+) T cells.
Nat Immunol. 2007 Dec 2;
Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) drive T helper type 1 (T(H)1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-gamma-induced transcription factor IRF1 was essential in T(H)1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor beta1 subunit (IL-12Rbeta1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4(+) T cells. Notably, the IRF1-dependent induction of IL-12Rbeta1 was essential for IFN-gamma-IL-12 signaling but was dispensable for IL-23-IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rbeta1, our data suggest that distinct thresholds of IL-12Rbeta1 expression are required for T(H)1 versus T(H)-17 differentiation. [Abstract]

Baba Y, Nishida K, Fujii Y, Hirano T, Hikida M, Kurosaki T
Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses.
Nat Immunol. 2007 Dec 2;
Mast cells have key functions as effectors of immunoglobulin E-mediated allergic inflammatory diseases. Allergen stimulation induces Ca(2+) influx and elicits the secretion of inflammatory mediators from mast cells. Here we show that the Ca(2+)-binding endoplasmic reticulum protein STIM1 is critical to mast cell function. STIM1-deficient fetal liver-derived mast cells had impaired Ca(2+) influx mediated by the high-affinity immunoglobulin E receptor FcepsilonRI and activation of the transcription factors NF-kappaB and NFAT. Mast cells lacking STIM1 also had much less degranulation and cytokine production after FcepsilonRI stimulation. In addition, alterations in STIM1 expression affected the sensitivity of immunoglobulin E-mediated immediate-phase anaphylactic responses in vivo. Thus, STIM1 is key in promoting the Ca(2+) influx that is essential for FcepsilonRI-mediated mast cell activation and anaphylaxis. [Abstract]

Depoil D, Fleire S, Treanor BL, Weber M, Harwood NE, Marchbank KL, Tybulewicz VL, Batista FD
CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand.
Nat Immunol. 2007 Dec 2;
Here we describe the spatiotemporal architecture, at high molecular resolution, of receptors and signaling molecules during the early events of mouse B cell activation. In response to membrane-bound ligand stimulation, antigen aggregation occurs in B cell antigen receptor (BCR) microclusters containing immunoglobulin (Ig) M and IgD that recruit the kinase Syk and transiently associate with the coreceptor CD19. Unexpectedly, CD19-deficient B cells were significantly defective in initiation of BCR-dependent signaling, accumulation of downstream effectors and cell spreading, defects that culminated in reduced microcluster formation. Hence, we have defined the dynamics of assembly of the main constituents of the BCR 'signalosome' and revealed an essential role for CD19, independent of the costimulatory molecule CD21, in amplifying early B cell activation events in response to membrane-bound ligand stimulation. [Abstract]

Vig M, Dehaven WI, Bird GS, Billingsley JM, Wang H, Rao PE, Hutchings AB, Jouvin MH, Putney JW, Kinet JP
Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels.
Nat Immunol. 2007 Dec 2;
CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release-activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which beta-galactosidase activity 'reported' CRACM1 expression. CRACM1-deficient mice were smaller in size. Mast cells derived from CRACM1-deficient mice showed grossly defective degranulation and cytokine secretion, and the allergic reactions elicited in vivo were inhibited in CRACM1-deficient mice. We detected robust CRACM1 expression in skeletal muscles and some regions of the brain, heart and kidney but not in the lymphoid regions of thymus and spleen. In contrast, we found CRACM2 expression to be much higher in mouse T cells. In agreement with those findings, the store-operated calcium influx and development and proliferation of CRACM1-deficient T cells was unaffected. Thus, CRACM1 is crucial in mouse mast cell effector function, but mouse T cell calcium release-activated calcium channels are functional in the absence of CRACM1. [Abstract]

Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, Merad M, Peche H, Lira SA, Ding Y, Yang Y, He X, Schuchman EH, Allende ML, Ochando JC, Bromberg JS
The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics.
Nat Immunol. 2007 Nov 25;
Although much is known about the migration of T cells from blood to lymph nodes, less is known about the mechanisms regulating the migration of T cells from tissues into lymph nodes through afferent lymphatics. Here we investigated T cell egress from nonlymphoid tissues into afferent lymph in vivo and developed an experimental model to recapitulate this process in vitro. Agonism of sphingosine 1-phosphate receptor 1 inhibited the entry of tissue T cells into afferent lymphatics in homeostatic and inflammatory conditions and caused the arrest, mediated at least partially by interactions of the integrin LFA-1 with its ligand ICAM-1 and of the integrin VLA-4 with its ligand VCAM-1, of polarized T cells at the basal surface of lymphatic but not blood vessel endothelium. Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress. [Abstract]

Cinamon G, Zachariah MA, Lam OM, Foss FW, Cyster JG
Follicular shuttling of marginal zone B cells facilitates antigen transport.
Nat Immunol. 2007 Nov 25;
The splenic marginal zone is a site of blood flow, and the specialized B cell population that inhabits this compartment has been linked to the capture and follicular delivery of blood-borne antigens. However, the mechanism of this antigen transport has remained unknown. Here we show that marginal zone B cells were not confined to the marginal zone but continuously shuttled between the marginal zone and follicular areas, such that many of the cells visited a follicle every few hours. Migration to the follicle required the chemokine receptor CXCR5, whereas return to the marginal zone was promoted by the sphingosine 1-phosphate receptors S1P(1) and S1P(3). Treatment with an S1P(1) antagonist caused displacement of marginal zone B cells from the marginal zone. Marginal zone-follicle shuttling of marginal zone B cells provides an efficient mechanism for systemic antigen capture and delivery to follicular dendritic cells. [Abstract]

Bansal G, Xie Z, Rao S, Nocka KH, Druey KM
Suppression of immunoglobulin E-mediated allergic responses by regulator of G protein signaling 13.
Nat Immunol. 2007 Nov 18;
Mast cells elicit allergic responses through degranulation and release of proinflammatory mediators after antigen crosslinking of the immunoglobulin E receptor FcepsilonRI. Proteins of the 'regulator of G protein signaling' (RGS) family negatively control signaling mediated by G protein-coupled receptors through GTPase-accelerating protein activity. Here we show that RGS13 inhibited allergic responses by physically interacting with the regulatory p85alpha subunit of phosphatidylinositol-3-OH kinase in mast cells and disrupting its association with an FcepsilonRI-activated scaffolding complex. Rgs13(-/-) mice had enhanced immunoglobulin E-mediated mast cell degranulation and anaphylaxis. Thus, RGS13 inhibits the assembly of immune receptor-induced signalosomes in mast cells. Abnormal RGS13 expression or function may contribute to disorders of amplified mast cell activity, such as idiopathic anaphylaxis. [Abstract]

Pamer EG
Erratum: Immune responses to commensal and environmental microbes.
Nat Immunol. 2007 Dec;8(12):1398. [Abstract]

Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, Stamatoyannopoulos JA, Wilson CB
Corrigendum: Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma.
Nat Immunol. 2007 Dec;8(12):1398. [Abstract]

Schwab SR, Cyster JG
Finding a way out: lymphocyte egress from lymphoid organs.
Nat Immunol. 2007 Dec;8(12):1295-1301.
The egress of lymphocytes from the thymus and secondary lymphoid organs into circulatory fluids is essential for normal immune function. The discovery that a small-molecule inhibitor of lymphocyte exit, FTY720, is a ligand for sphingosine 1-phosphate (S1P) receptors led to studies demonstrating that S1P receptor type 1 (S1P(1)) is needed in T cells and B cells for their egress from lymphoid organs. S1P exists in higher concentrations in blood and lymph than in lymphoid organs, and this differential is also required for lymphocyte exit. Transcriptional and post-translational mechanisms regulate S1P(1) and thus the egress of lymphocytes. In this review we discuss the body of evidence supporting a model in which lymphocyte egress is promoted by encounter with S1P at exit sites. We relate this model to work examining the effects of S1P receptor agonists on endothelium. [Abstract]

Research highlights.
Nat Immunol. 2007 Dec;8(12):1293. [Abstract]

Colucci F
Unexpected partnership between IL-15 and DAP10.
Nat Immunol. 2007 Dec;8(12):1289-91. [Abstract]

Takizawa H, Manz MG
Macrophage tolerance: CD47-SIRP-alpha-mediated signals matter.
Nat Immunol. 2007 Dec;8(12):1287-9. [Abstract]

Scheffold A, Murphy KM, Höfer T
Competition for cytokines: T(reg) cells take all.
Nat Immunol. 2007 Dec;8(12):1285-7. [Abstract]

Lederman MM, Sieg SF
CCR5 and its ligands: a new axis of evil?
Nat Immunol. 2007 Dec;8(12):1283-5. [Abstract]

Jankovic D, Trinchieri G
IL-10 or not IL-10: that is the question.
Nat Immunol. 2007 Dec;8(12):1281-3. [Abstract]

Strominger JL
Bacterial cell walls, innate immunity and immunoadjuvants.
Nat Immunol. 2007 Dec;8(12):1269-71. [Abstract]

Global scourge.
Nat Immunol. 2007 Dec;8(12):1267. [Abstract]

Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJ, O'Shea JJ, Hunter CA
Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.
Nat Immunol. 2007 Dec;8(12):1363-71.
Interleukin 10 (IL-10) has a prominent function in regulating the balance between protective and pathological T cell responses. Consistent with that activity, many sources of this cytokine are found in vivo, including from myeloid cells and a variety of T cell subsets. However, although there are many pathways that regulate innate production of IL-10, the factors that govern its synthesis by the adaptive response are poorly understood. Here we report that IL-27 and IL-6 induced T helper type 1 and type 2 cells, as well as T helper cells that produce IL-17, to secrete IL-10. This effect was dependent on the transcription factors STAT1 and STAT3 for IL-27 and on STAT3 for IL-6. Our studies identify a previously unknown pathway that allows the immune system to temper inflammatory responses. [Abstract]

McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ
TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
Nat Immunol. 2007 Dec;8(12):1390-7.
Studies have shown that transforming growth factor-beta (TGF-beta) and interleukin 6 (IL-6) are required for the lineage commitment of pathogenic IL-17-producing T helper cells (T(H)-17 cells). Unexpectedly, here we found that stimulation of myelin-reactive T cells with TGF-beta plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. Cells stimulated with TGF-beta plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. Hence, TGF-beta and IL-6 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of T(H)-17 cells. Our findings suggest that full acquisition of pathogenic function by effector T(H)-17 cells is mediated by IL-23 rather than by TGF-beta and IL-6. [Abstract]

Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, Saris CJ, Gran B, Ciric B, Rostami A
Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells.
Nat Immunol. 2007 Dec;8(12):1372-9.
Excessive inflammation occurs during infection and autoimmunity in mice lacking the alpha-subunit of the interleukin 27 (IL-27) receptor. The molecular mechanisms underlying this increased inflammation are incompletely understood. Here we report that IL-27 upregulated IL-10 in effector T cells that produced interferon-gamma and expressed the transcription factor T-bet but did not express the transcription factor Foxp3. These IFN-gamma(+)T-bet(+)Foxp3(-) cells resembled effector T cells that have been identified as the main source of host-protective IL-10 during inflammation. IL-27-induced production of IL-10 was associated with less secretion of IL-17, and exogenous IL-27 reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis by a mechanism dependent on IL-10. Our data show that IL-27-induced production of IL-10 by effector T cells contributes to the immunomodulatory function of IL-27. [Abstract]

Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL
A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.
Nat Immunol. 2007 Dec;8(12):1380-9.
Regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 are key in maintaining the balance of immune homeostasis. However, distinct induced T regulatory type 1 (Tr1) cells that lack Foxp3 expression also regulate T cell function, mainly by producing the immunosuppressive cytokine interleukin 10 (IL-10). However, the factors required for the induction of IL-10-producing suppressive T cells are not fully understood. Here we demonstrate that dendritic cells modified by T(reg) cells induced the generation of IL-10-producing Tr1 cells. The differentiation of naive CD4(+) T cells into IL-10-producing cells was mediated by IL-27 produced by the T(reg) cell-modified dendritic cells, and transforming growth factor-beta amplified the generation of induced IL-10(+) Tr1 cells by IL-27. Thus, IL-27 and transforming growth factor-beta promote the generation of IL-10-producing Tr1 cells. [Abstract]

Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS
Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells.
Nat Immunol. 2007 Dec;8(12):1313-23.
Graft failure in the transplantation of hematopoietic stem cells occurs despite donor-host genetic identity of human leukocyte antigens, suggesting that additional factors modulate engraftment. With the nobese diabetic (NOD)-severe combined immunodeficiency (SCID) xenotransplantation model, we found that the NOD background allowed better hematopoietic engraftment than did other strains with equivalent immunodeficiency-related mutations. We used positional genetics to characterize the molecular basis for this strain specificity and found that the NOD Sirpa allele conferred support for human hematopoiesis. NOD SIRP-alpha showed enhanced binding to the human CD47 ligand, and its expression on mouse macrophages was required for support of human hematopoiesis. Thus, we have identified Sirpa polymorphism as a potent genetic determinant of the engraftment of human hematopoietic stem cells. [Abstract]

Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ
CD4(+)CD25(+)Foxp3(+) regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4(+) T cells.
Nat Immunol. 2007 Dec;8(12):1353-62.
A key issue in mammalian immunology is how CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(reg) cells) suppress immune responses. Here we show that T(reg) cells induced apoptosis of effector CD4(+) T cells in vitro and in vivo in a mouse model of inflammatory bowel disease. T(reg) cells did not affect the early activation or proliferation of effector CD4(+) T cells. Cytokines that signal through the common gamma-chain suppressed T(reg) cell-induced apoptosis. T(reg) cell-induced effector CD4(+) T cell death required the proapoptotic protein Bim, and effector CD4(+) T cells incubated with T(reg) cells showed less activation of the prosurvival kinase Akt and less phosphorylation of the proapoptotic protein Bad. Thus, cytokine deprivation-induced apoptosis is a prominent mechanism by which T(reg) cells inhibit effector T cell responses. [Abstract]

Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E
Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor.
Nat Immunol. 2007 Dec;8(12):1337-44.
Consistent with their function in immune surveillance, natural killer (NK) cells are distributed throughout lymphoid and nonlymphoid tissues. However, the mechanisms governing the steady-state trafficking of NK cells remain unknown. The lysophospholipid sphingosine 1-phosphate (S1P), by binding to its receptor S1P(1), regulates the recirculation of T and B lymphocytes. In contrast, S1P(5) is detected in the brain and regulates oligodendrocyte migration and survival in vitro. Here we show that S1P(5) was also expressed in NK cells in mice and humans and that S1P(5)-deficient mice had aberrant NK cell homing during steady-state conditions. In addition, we found that S1P(5) was required for the mobilization of NK cells to inflamed organs. Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P(5). [Abstract]

Kaneider NC, Leger AJ, Agarwal A, Nguyen N, Perides G, Derian C, Covic L, Kuliopulos A
'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage.
Nat Immunol. 2007 Dec;8(12):1303-12.
Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis. [Abstract]

Dolan MJ, Kulkarni H, Camargo JF, He W, Smith A, Anaya JM, Miura T, Hecht FM, Mamtani M, Pereyra F, Marconi V, Mangano A, Sen L, Bologna R, Clark RA, Anderson SA, Delmar J, O'Connell RJ, Lloyd A, Martin J, Ahuja SS, Agan BK, Walker BD, Deeks SG, Ahuja SK
CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms.
Nat Immunol. 2007 Dec;8(12):1324-1336.
Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms. [Abstract]

Horng T, Bezbradica JS, Medzhitov R
NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway.
Nat Immunol. 2007 Dec;8(12):1345-1352.
The effector functions of natural killer cells are regulated by activating receptors, which recognize stress-inducible ligands expressed on target cells and signal through association with signaling adaptors. Here we developed a mouse model in which a fusion of the signaling adaptor DAP10 and ubiquitin efficiently downregulated expression of the activating receptor NKG2D on the surfaces of natural killer cells. With this system, we identified coupling of the signaling pathways triggered by NKG2D and DAP10 to those initiated by the interleukin 15 receptor. We suggest that this coupling of activating receptors to other receptor systems could function more generally to regulate cell type-specific signaling events in distinct physiological contexts. [Abstract]

Recent Articles in The Journal of Experimental Medicine

Di Noia JM, Williams GT, Chan DT, Buerstedde JM, Baldwin GS, Neuberger MS
Dependence of antibody gene diversification on uracil excision.
J Exp Med. 2007 Dec 10;
Activation-induced deaminase (AID) catalyses deamination of deoxycytidine to deoxyuridine within immunoglobulin loci, triggering pathways of antibody diversification that are largely dependent on uracil-DNA glycosylase (uracil-N-glycolase [UNG]). Surprisingly efficient class switch recombination is restored to ung(-/-) B cells through retroviral delivery of active-site mutants of UNG, stimulating discussion about the need for UNG's uracil-excision activity. In this study, however, we find that even with the overexpression achieved through retroviral delivery, switching is only mediated by UNG mutants that retain detectable excision activity, with this switching being especially dependent on MSH2. In contrast to their potentiation of switching, low-activity UNGs are relatively ineffective in restoring transversion mutations at C:G pairs during hypermutation, or in restoring gene conversion in stably transfected DT40 cells. The results indicate that UNG does, indeed, act through uracil excision, but suggest that, in the presence of MSH2, efficient switch recombination requires base excision at only a small proportion of the AID-generated uracils in the S region. Interestingly, enforced expression of thymine-DNA glycosylase (which can excise U from U:G mispairs) does not (unlike enforced UNG or SMUG1 expression) potentiate efficient switching, which is consistent with a need either for specific recruitment of the uracil-excision enzyme or for it to be active on single-stranded DNA. [Abstract]

Alexander-Brett JM, Fremont DH
Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor.
J Exp Med. 2007 Dec 10;
Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse gamma-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein-coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokine. Favorable electrostatic forces dramatically enhance the association kinetics of chemokines binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking. [Abstract]

O'Neil J, Tchinda J, Gutierrez A, Moreau L, Maser RS, Wong KK, Li W, McKenna K, Liu XS, Feng B, Neuberg D, Silverman L, Deangelo DJ, Kutok JL, Rothstein R, Depinho RA, Chin L, Lee C, Look AT
Alu elements mediate MYB gene tandem duplication in human T-ALL.
J Exp Med. 2007 Dec 10;
Recent studies have demonstrated that the MYB oncogene is frequently duplicated in human T cell acute lymphoblastic leukemia (T-ALL). We find that the human MYB locus is flanked by 257-bp Alu repeats and that the duplication is mediated somatically by homologous recombination between the flanking Alu elements on sister chromatids. Nested long-range PCR analysis indicated a low frequency of homologous recombination leading to MYB tandem duplication in the peripheral blood mononuclear cells of approximately 50% of healthy individuals, none of whom had a MYB duplication in the germline. We conclude that Alu-mediated MYB tandem duplication occurs at low frequency during normal thymocyte development and is clonally selected during the molecular pathogenesis of human T-ALL. [Abstract]

Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA
Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome.
J Exp Med. 2007 Dec 10;
Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa-induced cell death and release of the proinflammatory cytokine interleukin (IL)-1beta. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1-driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response. [Abstract]

Six EM, Bonhomme D, Monteiro M, Beldjord K, Jurkowska M, Cordier-Garcia C, Garrigue A, Dal Cortivo L, Rocha B, Fischer A, Cavazzana-Calvo M, André-Schmutz I
A human postnatal lymphoid progenitor capable of circulating and seeding the thymus.
J Exp Med. 2007 Dec 10;
Identification of a thymus-seeding progenitor originating from human bone marrow (BM) constitutes a key milestone in understanding the mechanisms of T cell development and provides new potential for correcting T cell deficiencies. We report the characterization of a novel lymphoid-restricted subset, which is part of the lineage-negative CD34(+)CD10(+) progenitor population and which is distinct from B cell-committed precursors (in view of the absence of CD24 expression). We demonstrate that these Lin(-)CD34(+)CD10(+)CD24(-) progenitors have a very low myeloid potential but can generate B, T, and natural killer lymphocytes and coexpress recombination activating gene 1, terminal deoxynucleotide transferase, PAX5, interleukin 7 receptor alpha, and CD3epsilon. These progenitors are present in the cord blood and in the BM but can also be found in the blood throughout life. Moreover, they belong to the most immature thymocyte population. Collectively, these findings unravel the existence of a postnatal lymphoid-polarized population that is capable of migrating from the BM to the thymus. [Abstract]

Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, Jeong JO, Curry C, Qin G, Yoon YS
Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart.
J Exp Med. 2007 Dec 10;
Noncellular differentiation effects have emerged as important mechanisms mediating therapeutic effects of stem or progenitor cell transplantation. Here, we investigated the expression patterns and sources of humoral factors and their regional and systemic biological effects after bone marrow (BM)-derived endothelial progenitor cell (EPC) transplantation into ischemic myocardium. Although most of the transplanted EPCs disappeared within a week, up-regulation of multiple humoral factors was sustained for longer than two weeks, which correlated well with the recovery of cardiac function. To determine the source of the humoral factors, we injected human EPCs into immunodeficient mice. Whereas the expression of human EPC (donor)-derived cytokines rapidly decreased to a nondetectable level within a week, up-regulation of mouse (recipient)-derived cytokines, including factors that could mobilize BM cells, was sustained. Histologically, we observed higher capillary density, a higher proliferation of myocardial cells, a lower cardiomyocyte apoptosis, and reduced infarct size. Furthermore, after EPC transplantation, BM-derived stem or progenitor cells were increased in the peripheral circulation and incorporated into the site of neovascularization and myocardial repair. These data indicate that myocardial EPC transplantation induces humoral effects, which are sustained by host tissues and play a crucial role in repairing myocardial injury. [Abstract]

Liang H, Coles AH, Zhu Z, Zayas J, Jurecic R, Kang J, Jones SN
Noncanonical Wnt signaling promotes apoptosis in thymocyte development.
J Exp Med. 2007 Dec 10;
The Wnt-beta-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt-Ca(2+) signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of alphabeta lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4(+)CD8(+) thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting beta-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of beta-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt-Ca(2+) pathway alters canonical Wnt signaling and is critical for normal T cell development. [Abstract]

Bates JG, Cado D, Nolla H, Schlissel MS
Chromosomal position of a VH gene segment determines its activation and inactivation as a substrate for V(D)J recombination.
J Exp Med. 2007 Dec 3;
Complete IgHC gene rearrangement occurs only in B cells in a stage-specific and ordered manner. We used gene targeting to reposition a distal V(H) gene segment to a region just 5' of the D(H) gene cluster and found its activation to be highly dependent on the chromosomal domain within which it resides. The targeted V(H) gene segment rearranged at a higher frequency than its endogenous counterpart, its rearrangement was no longer ordered, and its ability to be silenced by allelic exclusion was lost. Additionally, the targeted V(H) gene segment lost lineage specificity, as VDJ(H) rearrangement was observed in thymocytes. These data suggest that locus contraction, mimicked by proximal targeting, can override any regulation imposed by DNA sequences immediately surrounding V(H) gene segments. [Abstract]

Matus S, Burgos PV, Bravo-Zehnder M, Kraft R, Porras OH, Farías P, Barros LF, Torrealba F, Massardo L, Jacobelli S, González A
Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis.
J Exp Med. 2007 Dec 3;
The interesting observation was made 20 years ago that psychotic manifestations in patients with systemic lupus erythematosus are associated with the production of antiribosomal-P protein (anti-P) autoantibodies. Since then, the pathogenic role of anti-P antibodies has attracted considerable attention, giving rise to long-term controversies as evidence has either contradicted or confirmed their clinical association with lupus psychosis. Furthermore, a plausible mechanism supporting an anti-P-mediated neuronal dysfunction is still lacking. We show that anti-P antibodies recognize a new integral membrane protein of the neuronal cell surface. In the brain, this neuronal surface P antigen (NSPA) is preferentially distributed in areas involved in memory, cognition, and emotion. When added to brain cellular cultures, anti-P antibodies caused a rapid and sustained increase in calcium influx in neurons, resulting in apoptotic cell death. In contrast, astrocytes, which do not express NSPA, were not affected. Injection of anti-P antibodies into the brain of living rats also triggered neuronal death by apoptosis. These results demonstrate a neuropathogenic potential of anti-P antibodies and contribute a mechanistic basis for psychiatric lupus. They also provide a molecular target for future exploration of this and other psychiatric diseases. [Abstract]

Davila M, Liu F, Cowell LG, Lieberman AE, Heikamp E, Patel A, Kelsoe G
Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro B cells.
J Exp Med. 2007 Dec 3;
Receptor editing is believed to play the major role in purging newly formed B cell compartments of autoreactivity by the induction of secondary V(D)J rearrangements. In the process of immunoglobulin heavy (H) chain editing, these secondary rearrangements are mediated by direct V(H)-to-J(H) joining or cryptic recombination signals (cRSs) within V(H) gene segments. Using a statistical model of RS, we have identified potential cRSs within V(H) gene segments at conserved sites flanking complementarity-determining regions 1 and 2. These cRSs are active in extrachromosomal recombination assays and cleaved during normal B cell development. Cleavage of multiple V(H) cRSs was observed in the bone marrow of C57BL/6 and RAG2:GFP and muMT congenic animals, and we determined that cRS cleavage efficiencies are 30-50-fold lower than a physiological RS. cRS signal ends are abundant in pro-B cells, including those recovered from muMT mice, but undetectable in pre- or immature B cells. Thus, V(H) cRS cleavage regularly occurs before the generation of functional preBCR and BCR. Conservation of cRSs distal from the 3' end of V(H) gene segments suggests a function for these cryptic signals other than V(H) gene replacement. [Abstract]

Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P
Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma.
J Exp Med. 2007 Dec 3;
Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling. [Abstract]

Norrby E
Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine.
J Exp Med. 2007 Nov 26;204(12):2779-84.
In 1951, Max Theiler of the Rockefeller Foundation received the Nobel Prize in Physiology or Medicine for his discovery of an effective vaccine against yellow fever--a discovery first reported in the JEM 70 years ago. This was the first, and so far the only, Nobel Prize given for the development of a virus vaccine. Recently released Nobel archives now reveal how the advances in the yellow fever vaccine field were evaluated more than 50 years ago, and how this led to a prize for Max Theiler. [Abstract]

Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, Williams IR, Koval M, Peatman E, Campbell JA, Dermody TS, Nusrat A, Parkos CA
JAM-A regulates permeability and inflammation in the intestine in vivo.
J Exp Med. 2007 Nov 26;
Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A-deficient (JAM-A(-/-)) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A(-/-) mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A(-/-) mice. The in vivo observations were epithelial specific, because monolayers of JAM-A(-/-) epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A(-/-) mice and in JAM-A small interfering RNA-treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A(-/-) mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A(-/-) animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation. [Abstract]

Meyer-Bahlburg A, Khim S, Rawlings DJ
B cell intrinsic TLR signals amplify but are not required for humoral immunity.
J Exp Med. 2007 Nov 26;
Although innate signals driven by Toll-like receptors (TLRs) play a crucial role in T-dependent immune responses and serological memory, the precise cellular and time-dependent requirements for such signals remain poorly defined. To directly address the role for B cell-intrinsic TLR signals in these events, we compared the TLR response profile of germinal center (GC) versus naive mature B cell subsets. TLR responsiveness was markedly up-regulated during the GC reaction, and this change correlated with altered expression of the key adaptors MyD88, Mal, and IRAK-M. To assess the role for B cell-intrinsic signals in vivo, we transferred MyD88 wild-type or knockout B cells into B cell-deficient muMT mice and immunized recipient animals with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma globulin. All recipients exhibited similar increases in NP-specific antibody titers during primary, secondary, and long-term memory responses. The addition of lipopolysaccharide to the immunogen enhanced B cell-intrinsic, MyD88-dependent NP-specific immunoglobulin (Ig)M production, whereas NP-specific IgG increased independently of TLR signaling in B cells. Our data demonstrate that B cell-intrinsic TLR responses are up-regulated during the GC reaction, and that this change significantly promotes antigen-specific IgM production in association with TLR ligands. However, B cell-intrinsic TLR signals are not required for antibody production or maintenance. [Abstract]

Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Fariñas MS, Fuentes-Duculan J, Novitskaya I, Khatcherian A, Bluth MJ, Lowes MA, Krueger JG
Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
J Exp Med. 2007 Nov 26;
Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor-immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and beta-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon gamma, lymphotoxin alpha, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution. [Abstract]

Lichterfeld M, Kavanagh DG, Williams KL, Moza B, Mui SK, Miura T, Sivamurthy R, Allgaier R, Pereyra F, Trocha A, Feeney M, Gandhi RT, Rosenberg ES, Altfeld M, Allen TM, Allen R, Walker BD, Sundberg EJ, Yu XG
A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells.
J Exp Med. 2007 Nov 26;204(12):2813-24.
Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide-major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705-restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1-specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1-specific CD8+ T cells, the HLA-B2705-KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I-specific receptor expressed on myelomonocytic cells. Binding of the B2705-KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification. [Abstract]

Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, Streeck H, Waring M, Meier A, Brander C, Lifson JD, Allen TM, Carrington M, Altfeld M
Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes.
J Exp Med. 2007 Nov 26;204(12):3027-36.
Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)-B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact-dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I-dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication. [Abstract]

Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ
The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.
J Exp Med. 2007 Nov 26;204(12):3037-47.
Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6C(hi) and -6C(lo) monocytes via CCR2 and CX(3)CR1, respectively. Ly-6C(hi) monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6C(lo) monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular-endothelial growth factor. Consequently, Ly-6C(hi) monocytes digest damaged tissue, whereas Ly-6C(lo) monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6C(hi) monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI. [Abstract]

Guikema JE, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, Schrader CE
APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination.
J Exp Med. 2007 Nov 26;204(12):3017-26.
Antibody class switch recombination (CSR) occurs by an intrachromosomal deletion requiring generation of double-stranded breaks (DSBs) in switch-region DNA. The initial steps in DSB formation have been elucidated, involving cytosine deamination by activation-induced cytidine deaminase and generation of abasic sites by uracil DNA glycosylase. However, it is not known how abasic sites are converted into single-stranded breaks and, subsequently, DSBs. Apurinic/apyrimidinic endonuclease (APE) efficiently nicks DNA at abasic sites, but it is unknown whether APE participates in CSR. We address the roles of the two major mammalian APEs, APE1 and APE2, in CSR. APE1 deficiency causes embryonic lethality in mice; we therefore examined CSR and DSBs in mice deficient in APE2 and haploinsufficient for APE1. We show that both APE1 and APE2 function in CSR, resulting in the DSBs necessary for CSR and thereby describing a novel in vivo function for APE2. [Abstract]

Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T, Sakaguchi N, Sakaguchi S
Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model.
J Exp Med. 2007 Nov 26;204(12):2803-12.
This report shows that interleukin (IL) 17-producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor beta and IL-6 additionally need IL-1 and neutralization of interferon (IFN) gamma and IL-4 for CCR6 expression. Forced expression of RORgamma t, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1beta, IL-17, or tumor necrosis factor alpha, and is suppressed by IFN-gamma or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA. [Abstract]

Rossner M
JEM content to be deposited automatically in PubMed Central.
J Exp Med. 2007 Nov 26;204(12):2773. [Abstract]

McMichael AJ
Triple bypass: complicated paths to HIV escape.
J Exp Med. 2007 Nov 26;204(12):2785-8.
Human immunodeficiency virus (HIV) type 1 is highly efficient at evading immune responses and persisting, ultimately causing fatal immunodeficiency in some patients. Mutation in the epitopes recognized by cytolytic CD8+ T cells (CTLs) is one such escape process. A new study now shows that one HIV-1 escape mutation may also result in impaired dendritic cell (DC) activity, possibly impairing later T cell responses to the same and other epitopes. The new data complete our understanding of the mechanisms by which the CTL response to an immunodominant gag epitope presented by human histocompatibility leukocyte antigen (HLA)-B27 is evaded. The complexity of the full escape helps to explain why patients with this HLA type progress to AIDS more slowly than average. [Abstract]

Zhou JS, Xing W, Friend DS, Austen KF, Katz HR
Mast cell deficiency in Kit(W-sh) mice does not impair antibody-mediated arthritis.
J Exp Med. 2007 Nov 26;204(12):2797-802.
We previously reported that joint swelling, synovial thickening, and cartilage matrix depletion induced by the injection of anti-collagen monoclonal antibodies and lipopolysaccharide (LPS) in BALB/c mice are increased in the absence of inhibitory leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4; formerly gp49B1) in a neutrophil-dependent manner. Because both mast cells and neutrophils express LILRB4, we sought a mast cell requirement with mast cell-deficient mouse strains, but unexpectedly obtained full arthritis in Kit(W-sh) mice and full resistance in Kit(W/KitW-v) mice. Kit(W-sh) mice were indeed mast cell deficient as assessed by histology and the absence of IgE/mast cell-dependent passive cutaneous anaphylaxis in the ear and joint as well as passive systemic anaphylaxis. Deletion of LILRB4 in Kit(W-sh) mice exacerbated anti-collagen/LPS-induced joint swelling that was abolished by neutrophil depletion, establishing a counterregulatory role for LILRB4 in the absence of mast cells. Whereas blood neutrophil levels and LPS-elicited tissue neutrophilia were equal in Kit(W-sh) and Kit+ mice, both were impaired in Kit(W/KitW-v) mice. Although both strains are mast cell deficient and protected from IgE-mediated anaphylactic reactions, their dramatically different responses to autoantibody-mediated, neutrophil-dependent immune complex arthritis suggest that other host differences determine the extent of mast cell involvement. Thus, a conclusion for an absolute mast cell role in a pathobiologic process requires evidence from both strains. [Abstract]

Takahashi K, Shibata T, Akashi-Takamura S, Kiyokawa T, Wakabayashi Y, Tanimura N, Kobayashi T, Matsumoto F, Fukui R, Kouro T, Nagai Y, Takatsu K, Saitoh S, Miyake K
A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
J Exp Med. 2007 Nov 26;204(12):2963-76.
Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A-/- mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A-/- bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses. [Abstract]

Kovalchuk AL, duBois W, Mushinski E, McNeil NE, Hirt C, Qi CF, Li Z, Janz S, Honjo T, Muramatsu M, Ried T, Behrens T, Potter M
AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements.
J Exp Med. 2007 Nov 26;204(12):2989-3001.
Activation-induced cytidine deaminase (AID) is required for immunoglobulin (Ig) class switch recombination and somatic hypermutation, and has also been implicated in translocations between Ig switch regions and c-Myc in plasma cell tumors in mice. We asked if AID is required for accelerated tumor development in pristane-treated Bcl-xL transgenic BALB/c mice deficient in AID (pBxAicda-/-). pBxAicda-/- mice developed tumors with a lower frequency (24 vs. 62%) and a longer mean latency (108 vs. 36 d) than AID-sufficient mice. The tumors appeared in oil granuloma tissue and did not form ascites. By interphase fluorescence in situ hybridization, six out of nine pBxAicda-/- primary tumors had T(12;15) and one had T(6;15) chromosomal translocations. Two tumors were transplantable and established as stable cell lines. Molecular and cytogenetic analyses showed that one had an unusual unbalanced T(12;15) translocation, with IgH Cmu and Pvt-1 oriented head to tail at the breakpoint, resulting in an elevated expression of c-Myc. In contrast, the second was T(12;15) negative, but had an elevated N-Myc expression caused by a paracentric inversion of chromosome 12. Thus, novel mechanisms juxtapose Ig and Myc-family genes in AID-deficient plasma cell tumors. [Abstract]

Albu DI, Feng D, Bhattacharya D, Jenkins NA, Copeland NG, Liu P, Avram D
BCL11B is required for positive selection and survival of double-positive thymocytes.
J Exp Med. 2007 Nov 26;204(12):3003-15.
Transcriptional control of gene expression in double-positive (DP) thymocytes remains poorly understood. We show that the transcription factor BCL11B plays a critical role in DP thymocytes by controlling positive selection of both CD4 and CD8 lineages. BCL11B-deficient DP thymocytes rearrange T cell receptor (TCR) alpha; however, they display impaired proximal TCR signaling and attenuated extracellular signal-regulated kinase phosphorylation and calcium flux, which are all required for initiation of positive selection. Further, provision of transgenic TCRs did not improve positive selection of BCL11B-deficient DP thymocytes. BCL11B-deficient DP thymocytes have altered expression of genes with a role in positive selection, TCR signaling, and other signaling pathways intersecting the TCR, which may account for the defect. BCL11B-deficient DP thymocytes also presented increased susceptibility to spontaneous apoptosis associated with high levels of cleaved caspase-3 and an altered balance of proapoptotic/prosurvival factors. This latter susceptibility was manifested even in the absence of TCR signaling and was only partially rescued by provision of the BCL2 transgene, indicating that control of DP thymocyte survival by BCL11B is nonredundant and, at least in part, independent of BCL2 prosurvival factors. [Abstract]

Schaller MA, Neupane R, Rudd BD, Kunkel SL, Kallal LE, Lincoln P, Lowe JB, Man Y, Lukacs NW
Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines.
J Exp Med. 2007 Nov 26;204(12):2925-34.
Recent data have indicated that an important instructive class of signals regulating the immune response is Notch ligand-mediated activation. Using quantitative polymerase chain reaction, we observed that only Delta-like 4 (dll4) was up-regulated on bone marrow-derived dendritic cells after respiratory syncytial virus (RSV) infection, and that it was dependent on MyD88-mediated pathways. Using a polyclonal antibody specific for dll4, the development of RSV-induced disease was examined. Animals treated with anti-dll4 had substantially increased airway hyperresponsiveness compared with control antibody-treated animals. When the lymphocytic lung infiltrate was examined, a significant increase in total CD4+ T cells and activated (perforin+) CD8+ T cells was observed. Isolated lung CD4+ T cells demonstrated significant increases in Th2-type cytokines and a decrease in interferon gamma, demonstrating an association with increased disease pathogenesis. Parallel in vitro studies examining the integrated role of dll4 with interleukin-12 demonstrated that, together, both of these instructive signals direct the immune response toward a more competent, less pathogenic antiviral response. These data demonstrate that dll4-mediated Notch activation is one regulator of antiviral immunity. [Abstract]

Alcázar I, Marqués M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF
Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation.
J Exp Med. 2007 Nov 26;204(12):2977-87.
Class I phosphoinositide 3-kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase-associated receptors or G protein-coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class I(A) p85/p110 heterodimers, which are activated by Tyr kinases, and the class I(B) p110gamma isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase-associated receptor, p110gamma deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110gamma, as well as the consequences of interfering with p110gamma expression or function for T cell activation. We found that after TCR ligation, p110gamma interacts with G alpha(q/11), lymphocyte-specific Tyr kinase, and zeta-associated protein. TCR stimulation activates p110gamma, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110gamma controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110gamma in TCR-induced T cell activation. [Abstract]

Roy MF, Riendeau N, Bédard C, Hélie P, Min-Oo G, Turcotte K, Gros P, Canonne-Hergaux F, Malo D
Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice.
J Exp Med. 2007 Nov 26;204(12):2949-61.
The mouse response to acute Salmonella typhimurium infection is complex, and it is under the influence of several genes, as well as environmental factors. In a previous study, we identified two novel Salmonella susceptibility loci, Ity4 and Ity5, in a (AcB61 x 129S6)F2 cross. The peak logarithm of odds score associated with Ity4 maps to the region of the liver and red blood cell (RBC)-specific pyruvate kinase (Pklr) gene, which was previously shown to be mutated in AcB61. During Plasmodium chabaudi infection, the Pklr mutation protects the mice against this parasite, as indicated by improved survival and lower peak parasitemia. Given that RBC defects have previously been associated with resistance to malaria and susceptibility to Salmonella, we hypothesized that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice. Using a fine mapping approach combined with complementation studies, comparative studies, and functional analysis, we show that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice through its effect on the RBC turnover and iron metabolism. [Abstract]

Graham DB, Stephenson LM, Lam SK, Brim K, Lee HM, Bautista J, Gilfillan S, Akilesh S, Fujikawa K, Swat W
An ITAM-signaling pathway controls cross-presentation of particulate but not soluble antigens in dendritic cells.
J Exp Med. 2007 Nov 26;204(12):2889-97.
Dendritic cells (DC) possess a unique capacity for presenting exogenous antigen on major histocompatibility class I, a process that is referred to as cross-presentation, which serves a critical role in microbial and tumor immunity. During cross-presentation, antigens derived from pathogen-infected or tumor cells are internalized and processed by DCs for presentation to cytotoxic T lymphocytes (CTLs). We demonstrate that a signaling pathway initiated by the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors DAP12 and FcRgamma utilizes the Vav family of Rho guanine nucleotide exchange factors (GEFs) for processing and cross-presentation of particulate, but not soluble, antigens by DCs. Notably, this novel pathway is crucial for processing and presentation of particulate antigens, such as those associated with Listeria monocytogenes bacteria, yet it is not required for antigen uptake. Mechanistically, we provide evidence that in DCs, Vav GEFs are essential to link ITAM-dependent receptors with the activation of the NOX2 complex and production of reactive oxygen species (ROS), which regulate phagosomal pH and processing of particulate antigens for cross-presentation. Importantly, we show that genetic disruption of the DAP12/FcRgamma-Vav pathway leads to antigen presentation defects that are more profound than in DCs lacking NOX2, suggesting that ITAM signaling also controls cross-presentation in a ROS-independent manner. [Abstract]

Recent Articles in Current Opinion in Immunology

Winau F, Quack C, Darmoise A, Kaufmann SH
Starring stellate cells in liver immunology.
Curr Opin Immunol. 2007 Dec 6;
Stellate cells are star-shaped cells located in the liver and mediate a multitude of primarily non-immunological functions. They play a pivotal role in the metabolism of vitamin A and store 80% of total body retinol. Upon activation, stellate cells differentiate to myofibroblasts for production of extracellular matrix, leading to liver fibrosis. Moreover, activated stellate cells regulate liver blood flow through vasoconstriction implicated in portal hypertension. Earlier work demonstrated stellate cell derived secretion of chemokines and cytokines such as transforming growth factor beta (TGF-beta), suggesting an association with immunological processes. Indeed, recent evidence indicated that hepatic stellate cells perform potent APC function for stimulation of NKT cells as well as CD8 and CD4 T cells. Additionally, stellate cell mediated antigen presentation induced protective immunity against bacterial infection. Current experiments reveal that the presenting ability of stellate cells is the key to antigen-dependent T cell instruction by vitamin A derived retinoic acid. Finally, future studies will show whether in the firmament of immunology stellate cells will represent fixed or falling stars. [Abstract]

De Libero G, Mori L
How T cells get grip on lipid antigens.
Curr Opin Immunol. 2007 Dec 5;
Lipid antigens are presented to T cells as complexes formed with CD1 family members. The hydrophobic nature of lipids influences how they remain in biological fluids, are distributed within cells, and are handled to become immunogenic. Continuously expanding knowledge shows how lipids are internalized by APC, traffic through the endocytic system, are processed to generate immunogenic molecules, and are loaded on CD1 proteins. The molecular bases of how lipids interact with CD1 and TCR are being defined. A breakthrough in the field has been the discovery that exogenous and endogenous lipids stimulate T cells which mount adaptive and innate-like responses. Disclosure of molecular protagonists and mechanisms of both responses has great promise for development of novel lipid-based vaccines and immunotherapies. [Abstract]

von Landenberg P, Bauer S
Nucleic acid recognizing Toll-like receptors and autoimmunity.
Curr Opin Immunol. 2007 Nov 28;
The understanding of autoimmune diseases experienced an impressive boost since the Toll-like receptors (TLRs) have been identified as possible key players in autoimmune pathophysiology. Although these receptors recognize a variety of structures derived from viruses, bacteria, and fungi leading to subsequent initiation of the relevant immune responses, recent data support the idea that TLRs are crucial in the induction and perpetuation of certain autoimmune diseases, especially the systemic lupus erythematosus (SLE). In this review, we will summarize recent data on involvement of TLRs in the development of autoimmune diseases. We will focus on TLRs 7, 8, and 9 that were originally identified as receptors specific for bacterial and viral RNA/DNA, but more recent in vitro and in vivo studies have linked these receptors to the detection of host RNA, DNA, and RNA-associated or DNA-associated proteins in the context of autoimmunity. [Abstract]

Lin AE, Mak TW
The role of E3 ligases in autoimmunity and the regulation of autoreactive T cells.
Curr Opin Immunol. 2007 Nov 22;
The ubiquitination of proteins by E3 ligases has become an important regulatory mechanism for a variety of immune functions, including the maintenance of self tolerance and suppression of autoreactive T cell development. This review highlights recent advances in our knowledge of the functions in this context of known and potential E3 ligases, including autoimmune regulator (AIRE), TNF receptor-associated factor 6 (TRAF6), Casitas B cell lymphoma b (Cbl-b), gene related to anergy in lymphocytes (GRAIL), Itch, and Roquin. We discuss how disruptions to these molecules may contribute to the loss of T cell homeostasis and the pathogenesis of autoimmunity. We also report on the implications of the potential coordinated actions of these molecules for T cell anergy and regulatory T cell (Treg) functions. The great diversity of E3 ligases and the growing list of cellular processes in which ubiquitination plays a role make for an exciting field of research. Findings emerging from these investigations may suggest ways to exploit the therapeutic potential of manipulating ubiquitination, particularly for autoimmune disorders. [Abstract]

Allantaz F, Chaussabel D, Banchereau J, Pascual V
Microarray-based identification of novel biomarkers in IL-1-mediated diseases.
Curr Opin Immunol. 2007 Nov 22;
Interleukin 1b (IL-1b) is emerging as mediator of a wide range of human diseases. Availability of IL-1 blockers that result in clinical benefits to patients with these diseases is creating a demand for biomarkers to diagnose as well as to predict and follow responses to therapy. Blood gene expression profiling can be used to identify such biomarkers. This review will summarize recent studies in the field and will discuss some of the challenges raised by the use of this technology in biomarker discovery. [Abstract]

Clynes R
Protective mechanisms of IVIG.
Curr Opin Immunol. 2007 Nov 19; [Abstract]

Pétrilli V, Dostert C, Muruve DA, Tschopp J
The inflammasome: a danger sensing complex triggering innate immunity.
Curr Opin Immunol. 2007 Oct 29;
The NOD-like receptors (NLR) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. Several NLRs (NALPs and IPAF) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including IL-1beta. Amongst the various inflammasomes, the NALP3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. The important role of the NALP3 inflammasome is emphasized by the identification of mutations in the NALP3 gene that are associated with a susceptibility to inflammatory disorders. These and other issues related to the inflammasome are discussed in this review. [Abstract]

Kool M, Lambrecht BN
Dendritic cells in asthma and COPD: opportunities for drug development.
Curr Opin Immunol. 2007 Oct 29;
The lung contains many subsets of dendritic cells that are distributed in various anatomical compartments. In homeostatic conditions, a fine-tuned balance exists between plasmacytoid and myeloid dendritic cells necessary for maintaining tolerance to inhaled antigen and avoiding overt inflammation. These subsets of DCs also play important roles in establishment of airway inflammation seen in asthma and chronic obstructive pulmonary disease. Based on these new insights on airway DC biology, several approaches that interfere with DC function show potential as new intervention strategies for these ever increasing diseases. [Abstract]

Saibil SD, Deenick EK, Ohashi PS
The sound of silence: modulating anergy in T lymphocytes.
Curr Opin Immunol. 2007 Oct 17;
Understanding the intercellular and intracellular mechanisms that maintain anergy and prevent the induction of full effector function is one avenue that may allow us to manipulate immune responses. Recent studies of T cell receptor (TCR)-proximal signaling events in different models of T cell unresponsiveness have suggested that biochemically distinct forms of anergy may exist in vivo. T cell responsiveness can be altered through the control of the intracellular pool of key second messengers, such as diacylglycerol (DAG) or the lipid modification of signaling molecules, such as the Linker for activated T cells (LAT). Studies on the molecule programmed death-1 (PD-1) and its ligands have revealed that tissue-resident signals are essential in the maintenance of T cell unresponsiveness. Thus, the emerging view is that T cell anergy is a dynamic state whose establishment and maintenance can be influenced by numerous different signaling pathways. [Abstract]

Kariyawasam HH, Robinson DS
The role of eosinophils in airway tissue remodelling in asthma.
Curr Opin Immunol. 2007 Oct 17;
There is an increasing evidence that airway structural change (termed remodelling) is associated with the severity and chronicity of asthma. Recent studies support an important role for eosinophils in the remodelling process. In particular eosinophil depletion studies have demonstrated that several aspects of remodelling are attenuated. Eosinophils have been confirmed as an important source of TGF-beta(1) as well as other important cytokines that can lead to the direct activation of epithelium and mesenchymal cells that are considered to drive airway remodelling. The current studies that support a role for eosinophils in airway remodelling are reviewed in article. [Abstract]

Saito H
Allergy and hypersensitivity-airway inflammation and remodeling.
Curr Opin Immunol. 2007 Oct 11; [Abstract]

Kato A, Schleimer RP
Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity.
Curr Opin Immunol. 2007 Oct 8;
It has become increasingly clear that airway epithelial cells are central participants in innate and adaptive immune responses as well as mucosal inflammation. Epithelial cells produce antimicrobial host defense molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. Recruitment of immune cells including dendritic cells, T cells and B cells into the proximity of epithelium results in the enhancement of adaptive immunity through interactions with epithelial cells. Newly identified epithelial-derived cytokines, including TSLP, IL-33 and BAFF, help to shape the local accumulation and activation of Th2 responses and B cell immunoglobulin production. Epithelial cells are also downstream targets of molecules that activate IL-13R and EGFR and are responsible for mucus production in both protective immune responses and allergic airway inflammatory diseases. Improved understanding of epithelial immune and inflammatory responses will hopefully suggest new strategies for therapeutic intervention. [Abstract]

Marsland BJ, Kopf M
Toll-like receptors: paving the path to T cell-driven autoimmunity?
Curr Opin Immunol. 2007 Sep 20;
The development of autoimmunity is often associated with the presence of pathogen-associated molecular patterns (PAMPs) and signaling through toll-like receptors (TLRs). Largely, the importance of PAMP-TLR ligation has been attributed to inducing the maturation of antigen-presenting cells and production of proinflammatory cytokines and chemokines. Recent evidence now shows that PAMPs can activate effector and regulatory T cells revealing a further level of complexity in the development of autoimmunity. TLR signaling on T cells acts as a form of costimulation, lowering the 'strength of signal' required for proliferation and survival. This apparent mechanism of immune homeostasis may break tolerance or anergy upon pathogen infection and promote the development of immune responses against self-antigens. [Abstract]

Sambrook JG, Beck S
Evolutionary vignettes of natural killer cell receptors.
Curr Opin Immunol. 2007 Oct;19(5):553-60.
The discovery of novel immune receptors has led to a recent renaissance of research into the innate immune system, following decades of intense research of the adaptive immune system. Of particular interest has been the discovery of the natural killer (NK) cell receptors which, depending on type, interact with classical or non-classical MHC class I antigens of the adaptive immune system, thus functioning at the interface of innate and adaptive immunity. Here, we review recent progress with respect to two such families of NK receptors, the killer immunoglobulin-like receptors (KIRs) and the killer cell lectin-like receptors (KLRs), and attempt to trace their evolution across vertebrates. [Abstract]

Amemiya CT, Saha NR, Zapata A
Evolution and development of immunological structures in the lamprey.
Curr Opin Immunol. 2007 Oct;19(5):535-41.
Comparative immunology has been revitalized by the integration of genomics approaches, which allow a foothold into addressing problems that previously had been difficult to study. One such problem had been the enigmatic finding of overt immune anatomical structures in the lamprey, yet its apparent lack of bona fide immunoglobulin or T cell receptor molecules. The genomic characterization of a novel extended locus that undergoes rearrangements to generate receptor diversity and the subsequent implementation of this diversity in the immune system of lampreys have generated considerable interest as well as new avenues for investigation. Here, we review the anatomical structures of the lamprey that exhibit lympho-hematopoietic characteristics, with the ultimate goal of reconciling these data with contemporary molecular findings. By integrating these datasets we seek to better understand how an alternative adaptive immune system could have evolved. [Abstract]

Waldmann H
Curr Opin Immunol. 2007 Oct;19(5):561-2. [Abstract]

Bettelli E, Korn T, Kuchroo VK
Th17: the third member of the effector T cell trilogy.
Curr Opin Immunol. 2007 Aug 31;
T helper responses have now grown to include three T cell subsets: Th1, Th2 and Th17. Th17 cells have recently emerged as a third independent T cell subset that may play an essential role in protection against certain extracellular pathogens. However, Th17 cells with specificity for self-antigens are highly pathogenic and lead to the development of inflammation and severe autoimmunity. A combination of TGF-beta plus IL-6 and the transcription factors STAT3 and RORgammat were recently described to be essential for initial differentiation of Th17 cells and IL-23 for the later stabilization of the Th17 cell subset. Here, we introduce another player IL-21 produced by Th17 themselves, which plays an important role in the amplification of Th17 cells. Thus, Th17 cells may undergo three distinct steps of development: differentiation, amplification and stabilization in which distinct cytokines play a role. [Abstract]

Zhou W, Medof ME, Heeger PS, Sacks S
Graft-derived complement as a mediator of transplant injury.
Curr Opin Immunol. 2007 Oct;19(5):569-76. [Abstract]

Okayama Y, Ra C, Saito H
Role of mast cells in airway remodeling.
Curr Opin Immunol. 2007 Aug 28;
The extent of airway remodeling correlates with severity of asthma. Persistent airway hyperresponsiveness (AHR) is associated with airway remodeling, but not with inflammation. The increase in ASM mass is recognized as one of the most important factors related to AHR and to the severity of asthma. The infiltration of ASM by mast cells (MCs) is associated with the disordered airway function. The mediators such as tryptase and cytokines from MCs can modulate ASM cell function and induce goblet cell hyperplasia. MCs were found to contribute to the development of multiple features of chronic asthma in MC-deficient mice. Therefore, MCs play an important role not only in immediate hypersensitivity and late phase inflammation but also in tissue remodeling in the airway. [Abstract]

Adcock IM, Tsaprouni L, Bhavsar P, Ito K
Epigenetic regulation of airway inflammation.
Curr Opin Immunol. 2007 Aug 24;
Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by epigenetic changes. Transcriptional co-activators possess intrinsic histone acetyltransferase (HAT) activity, and histone acetylation plays a major role in inflammatory gene expression. Other marks such as histone methylation are also associated with gene induction and gene repression. Recent evidence implicates histone acetylation and methylation as being crucial for the development of tolerance in macrophages and CpG methylation for T regulatory cell development and function. The expression of the enzymes that lay down or remove these epigenetic marks have not been well studied in human airways disease, but reduced HDAC2 expression and activity is reported in lung macrophages, biopsies and blood cells from patients with COPD, severe asthma and smoking asthma. In vitro, inhibitors of histone deacetylases (HDAC) often lead to a further induction of inflammatory gene expression. This is not always the case, however, as HATs and HDACs also target non-histone proteins particularly transcription factors to alter their activity. Furthermore, trichostatin A, an HDAC inhibitor, can reduce inflammation in a murine model of allergic asthma. This effect of HDAC inhibitors may be due to their effects on cell death acting through acetylation of non-histone proteins. The role of epigenetic modifications in inflammatory gene expression and in the control of cell function in the airways is becoming clearer. Targeting specific enzymes involved in this process may lead to new therapeutic agents, in particular, in situations where current anti-inflammatory therapies are currently suboptimal. [Abstract]

Alegre ML, Florquin S, Goldman M
Cellular mechanisms underlying acute graft rejection: time for reassessment.
Curr Opin Immunol. 2007 Oct;19(5):563-8.
Rejection of transplanted organs depends on an orchestrated immune response to histocompatibility antigens expressed by the grafted tissue. Effector mechanisms primarily responsible for the rejection process classically involve type 1 helper CD4(+) T cells, cytotoxic CD8(+) T cells and antibodies. Experimental studies revealed alternative mechanisms of rejection that implicate type 2 helper CD4(+) T cells and memory CD8(+) T cells as well as cells belonging to the innate immune system including natural killer cells, eosinophils and neutrophils. Furthermore, local inflammation associated with rejection is tightly regulated at the graft level by regulatory T cells and mast cells. The redundancy of rejection mechanisms explains the difficulty to induce transplantation tolerance and to develop reliable biomarkers for prediction of allograft outcome. [Abstract]

Doherty T, Broide D
Cytokines and growth factors in airway remodeling in asthma.
Curr Opin Immunol. 2007 Aug 24;
Airway remodeling in asthma is defined by several structural changes including epithelial cell mucus metaplasia, an increase in peribronchial smooth muscle mass, subepithelial fibrosis, and angiogenesis. Cytokines, chemokines, and growth factors released from inflammatory and structural cells in the airway are considered to play a pivotal role in the development of remodeling. Studies of allergen induced airway remodeling in transgenic mice suggest an important role for TGF-beta, VEGF, Th2 cytokines (IL-5, IL-9, IL-13), and epithelial derived NF-kappaB regulated chemokines in airway remodeling. Although studies of bronchial biopsies from human asthmatics also demonstrate expression of TGF-beta, VEGF, IL-5, IL-9, IL-13, and NF-kappaB regulated chemokines, further human intervention studies are required in which individual cytokines or chemokines are neutralized to define their role in airway remodeling. [Abstract]

Tao R, de Zoeten EF, Ozkaynak E, Wang L, Li B, Greene MI, Wells AD, Hancock WW
Histone deacetylase inhibitors and transplantation.
Curr Opin Immunol. 2007 Oct;19(5):589-95.
Simply detecting the presence or absence of Foxp3, a transcription factor characteristic of naturally occurring CD4+ CD25+ regulatory T cells (Tregs), now appears of minimal value in predicting the outcome of immunologic responses, since dividing human CD4+ effector T cells can induce Foxp3 without attaining repressive functions, and additional molecular interactions, as well epigenetic events, affect Foxp3-dependent Treg functions in humans and mice. Experimentally, in vivo and in vitro studies show histone deacetylase inhibitors (HDACi) can enhance the numbers and suppressive function of regulatory T cells (Tregs) by promoting Foxp3+ cell production, enhancing chromatin remodeling within Tregs, and inducing acetylation of Foxp3 protein itself. Human studies consistent with a role for HDACi in controlling Fox3-dependent Treg functions are also available. We review these molecular interactions and how they may be exploited therapeutically to enhance Treg-dependent functions, including post-transplantation. [Abstract]

Flajnik MF
Immunogenetics: alternative strategies in adaptive immunity and the rise of comparative immunogenomics.
Curr Opin Immunol. 2007 Oct;19(5):522-5. [Abstract]

Strasser A
Haematopoietic cell apoptosis.
Curr Opin Immunol. 2007 Oct;19(5):485-7. [Abstract]

Streblow DN, Orloff SL, Nelson JA
Acceleration of allograft failure by cytomegalovirus.
Curr Opin Immunol. 2007 Oct;19(5):577-82.
A number of human herpesviruses are important opportunistic pathogens that have been associated with increased morbidity and mortality in transplant recipients including human cytomegalovirus (HCMV), HHV6, HHV7, HHV8 as well as HSV-1, VZV. However, HCMV has been linked both epidemiologically and through the use of animal models to the acceleration of acute and chronic allograft rejection. This review will cover the pathophysiology, epidemiology, and mechanisms of CMV-associated disease in the setting of transplantation. [Abstract]

Fairchild PJ, Robertson NJ, Minger SL, Waldmann H
Embryonic stem cells: protecting pluripotency from alloreactivity.
Curr Opin Immunol. 2007 Oct;19(5):596-602.
There can be little doubt that 2006 turned out to be the annus horribilis for therapeutic cloning by somatic nuclear transfer (SNT). As the full extent of the fraud surrounding the generation of patient-specific embryonic stem (ES) cell lines became apparent, hopes began to fade for the advent of cell replacement therapies (CRT), free from the confounding issues of immune rejection. While the dust begins to settle, it is perhaps pertinent to ask whether the promise of SNT is still worth pursuing or whether alternative strategies for immune evasion might help fill the void. [Abstract]

Naghavi MH, Goff SP
Retroviral proteins that interact with the host cell cytoskeleton.
Curr Opin Immunol. 2007 Aug;19(4):402-7.
In the past decade, several lines of evidence have highlighted the importance of the host cell cytoskeleton in various stages of retroviral infection. To complete their lifecycle, retroviruses must penetrate the outer barrier of the cell membrane, and viral cores containing the viral genome must traverse the cytoplasm to the nucleus and then viral gene products must make the journey back to the cell surface in order to release new progeny. The presence of a dense cytoskeletal network and organelles in the cytoplasm creates an environment that greatly impedes diffusion of macromolecules such as viruses. As such, retroviruses have evolved means to hijack actin as well as microtubule cytoskeletal networks that regulate macromolecular movement within the host cell. Developing studies are discovering several host and viral factors that play important roles in retroviral trafficking. [Abstract]

Kasahara M
The 2R hypothesis: an update.
Curr Opin Immunol. 2007 Oct;19(5):547-52.
Nearly forty years ago, Susumu Ohno proposed that one or two rounds of whole genome duplication took place close to the origin of vertebrates. The refined version of this proposal, known as the two round (2R) hypothesis, assumes that the genome of jawed vertebrates has been shaped by two rounds of whole genome duplication that took place after the emergence of urochordates and before the radiation of jawed vertebrates. Although this hypothesis has been a focus of heated debate in recent years, it is increasingly supported by genome-wide analysis of key chordate species. The 2R hypothesis has important implications for understanding the evolution of the immune system, including the origin of the major histocompatibility complex and natural killer receptors. [Abstract]

Litman GW, Dishaw LJ, Cannon JP, Haire RN, Rast JP
Alternative mechanisms of immune receptor diversity.
Curr Opin Immunol. 2007 Oct;19(5):526-34.
Our views of both innate and adaptive immunity have been significantly modified by recent studies of immune receptors and immunity in protostomes, invertebrate deuterostomes, and jawless vertebrates. Extraordinary variation in the means whereby organisms recognize pathogens has been revealed by a series of recent findings, including: novel forms of familiar immune receptors, high genetic polymorphism for new receptor types, germline rearrangement for non-Ig domain receptors, somatic variation of germline-encoded receptors, and unusually complex alternative splicing of genes with both immune and non-immune roles. Collectively, these observations underscore heretofore unrecognized pathways in the evolution of immune recognition and suggest universal processes by which immune systems co-opt and integrate existing cellular mechanisms to effect diverse recognition functions. [Abstract]

Recent Articles in Journal of Immunology

Zhou Y, Gong B, Lin F, Rother RP, Medof ME, Kaminski HJ
Anti-c5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis.
J Immunol. 2007 Dec 15;179(12):8562-7.
Myasthenia gravis (MG) is a neuromuscular transmission disorder in which damage to acetylcholine receptors (AChR) on motor endplates by autoantibody-induced complement attack causes muscle weakness. To determine whether and, if so, to what extent, blockade of complement cascade at the C5 step ameliorates disease, we evaluated the effect of administering a functionally blocking anti-C5 mAb in passive experimental MG in Lewis rats induced with AChR Ab McAb-3. In contrast to uniform severe weakness at 24 h requiring euthanasia in untreated animals, anti-C5 mAb-pretreated rats showed no weakness at 48 h. Anti-C5 mAb treatment 24 h after disease induction restored strength in two-thirds of the rats. Immunofluorescence staining of endplates from the treated animals showed that C9 deposition at AChR was reduced and ultrastructural analyses showed that endplates were intact. The results argue that targeting C5 may warrant testing in MG patients and that this approach may be particularly valuable for myasthenic crisis. [Abstract]

Kishida T, Hiromura Y, Shin-Ya M, Asada H, Kuriyama H, Sugai M, Shimizu A, Yokota Y, Hama T, Imanishi J, Hisa Y, Mazda O
IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice.
J Immunol. 2007 Dec 15;179(12):8554-61.
IL-21 exerts pleiotrophic immunomodulatory activities on a variety of target cells including B cells that undergo class switch recombination (CSR) to IgE. In this study, we examined whether IgE-mediated systemic anaphylaxis was controlled by in vivo administration of IL-21 using the peanut allergy model in mice and investigated the molecular mechanisms underlying the IL-21-induced regulation of IgE. The anaphylactic reaction was completely abolished by the administration of recombinant mouse IL-21 or an IL-21 expression plasmid in terms of the change of body temperature and anaphylactic symptoms. The recombinant mouse IL-21 treatment remarkably suppressed IgE CSR in splenic B cells, resulting in significant decrease in serum concentrations of total as well as allergen-specific IgE. In the meanwhile, IL-21 provoked B cells in normal as well as allergic mice to express the inhibitor of differentiation 2 (Id2) gene that was shown to be crucially involved in the regulation of the activation-induced cytidine deaminase and IgE CSR. Moreover, mice genetically deficient for Id2 were completely unsusceptible to IL-21-induced prevention of IgE CSR and anaphylaxis. The present study strongly suggests that IL-21 is capable of regulating systemic allergic reactions by inducing the transcriptional regulator Id2, and the cytokine may be useful for clinical intervention for allergic diseases including anaphylaxis. [Abstract]

Vaughan KR, Stokes L, Prince LR, Marriott HM, Meis S, Kassack MU, Bingle CD, Sabroe I, Surprenant A, Whyte MK
Inhibition of Neutrophil Apoptosis by ATP Is Mediated by the P2Y11 Receptor.
J Immunol. 2007 Dec 15;179(12):8544-53.
Neutrophils undergo rapid constitutive apoptosis that is delayed by a range of pathogen- and host-derived inflammatory mediators. We have investigated the ability of the nucleotide ATP, to which neutrophils are exposed both in the circulation and at sites of inflammation, to modulate the lifespan of human neutrophils. We found that physiologically relevant concentrations of ATP cause a concentration-dependent delay of neutrophil apoptosis (assessed by morphology, annexin V/To-Pro3 staining, and mitochondrial membrane permeabilization). We found that even brief exposure to ATP (10 min) was sufficient to cause a long-lasting delay of apoptosis and showed that the effects were not mediated by ATP breakdown to adenosine. The P2 receptor mediating the antiapoptotic actions of ATP was identified using a combination of more selective ATP analogs, receptor expression studies, and study of downstream signaling pathways. Neutrophils were shown to express the P2Y(11) receptor and inhibition of P2Y(11) signaling using the antagonist NF157 abrogated the ATP-mediated delay of neutrophil apoptosis, as did inhibition of type I cAMP-dependent protein kinases activated downstream of P2Y(11), without effects on constitutive apoptosis. Specific targeting of P2Y(11) could retain key immune functions of neutrophils but reduce the injurious effects of increased neutrophil longevity during inflammation. [Abstract]

Souza DG, Fagundes CT, Amaral FA, Cisalpino D, Sousa LP, Vieira AT, Pinho V, Nicoli JR, Vieira LQ, Fierro IM, Teixeira MM
The required role of endogenously produced lipoxin a4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice.
J Immunol. 2007 Dec 15;179(12):8533-43.
The appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A(4) and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A(4) analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF-alpha production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A(4) and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A(4) and annexin-1. Blockade of lipoxin A(4) synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A(4) and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF-alpha production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A(4) and annexin-1. [Abstract]

Pedrazzi M, Patrone M, Passalacqua M, Ranzato E, Colamassaro D, Sparatore B, Pontremoli S, Melloni E
Selective proinflammatory activation of astrocytes by high-mobility group box 1 protein signaling.
J Immunol. 2007 Dec 15;179(12):8525-32.
Extracellular high-mobility group box 1 protein (HMGB1) triggers inflammatory events in the brain. We demonstrate that astrocytes, the main glial cells in the brain, acquire a specific reactive phenotype when exposed to HMGB1. This cell activation, which involves the receptor for advanced glycation end-products and the MAPK/ERK1/2 cascade, results in the transcriptional/translational induction of a restricted number of inflammatory mediators, including cyclooxygenase-2, matrix metalloproteinase-9, and several chemokines of the CC and CXC families. The mixture of factors released by HMGB1-reactive astrocytes displays a potent chemotactic activity on human monocytic cells. This study is the first to suggest that HMGB1/astrocyte interaction plays a specific functional role in the progression of inflammatory processes in the CNS by facilitating local leukocyte infiltration. [Abstract]

Fontalba A, Gutierrez O, Fernandez-Luna JL
NLRP2, an Inhibitor of the NF-{kappa}B Pathway, Is Transcriptionally Activated by NF-{kappa}B and Exhibits a Nonfunctional Allelic Variant.
J Immunol. 2007 Dec 15;179(12):8519-24.
NLRP2 has been shown to inhibit the NF-kappaB signaling pathway, and thus may contribute to modulate the inflammatory response, where NF-kappaB plays a major role. In this study, we report that expression of NLRP2 is induced upon differentiation of CD34(+) hemopoietic progenitors into granulocyte or monocyte/macrophages. We also found that NLRP2 was up-regulated following differentiation of mesenchymal stem cells toward adipocytes. Notably, stimulation of HEK293T cells with TNF-alpha or overexpression of the p65 subunit of NF-kappaB resulted in up-regulation of NLRP2 and the formation of NF-kappaB-NLRP2 promoter complexes. Moreover, ectopic expression of p65 but not of other transcriptional regulators induced transactivation of the NLRP2 promoter. Thus, NLRP2 may control NF-kappaB activation through a regulatory loop. Nucleotide changes within the NACHT domain of other NLRP proteins have been associated with hereditary fever syndromes and chronic inflammatory diseases. We identified five single nucleotide polymorphisms present in the NACHT domain of NLRP2 by sequencing genomic DNA from 319 healthy controls. The frequencies of the rare alleles varied between 0.2 and 10%. Of note, one of these variants, I352S was unable to block the transcriptional activity of NF-kappaB and the formation of NF-kappaB-DNA-binding complexes following stimulation with TNF-alpha. Overall, our findings provide molecular insight into the expression of NLRP2 by NF-kappaB and suggest that a polymorphism within the NACHT domain of NLRP2 may contribute to the amplification of inflammatory responses due to a reduction of inhibitory signals on the NF-kappaB pathway. [Abstract]

Gainers ME, Descheny L, Barthel SR, Liu L, Wurbel MA, Dimitroff CJ
Skin-Homing Receptors on Effector Leukocytes Are Differentially Sensitive to Glyco-Metabolic Antagonism in Allergic Contact Dermatitis.
J Immunol. 2007 Dec 15;179(12):8509-8518.
T cell recruitment into inflamed skin is dependent on skin-homing receptor binding to endothelial (E)- and platelet (P)-selectin. These T cell receptors, or E- and P-selectin ligands, can be targeted by the metabolic fluorosugar inhibitor, 4-F-GlcNAc, to blunt cutaneous inflammation. Compelling new data indicate that, in addition to T cells, NK cells are also recruited to inflamed skin in allergic contact hypersensitivity (CHS) contingent on E- and P-selectin-binding. Using a model of allergic CHS, we evaluated the identity and impact of NK cell E-selectin ligand(s) on inflammatory responses and examined the oral efficacy of 4-F-GlcNAc. We demonstrated that the predominant E-selectin ligands on NK cells are P-selectin glycoprotein ligand-1 and protease-resistant glycolipids. We showed that, unlike the induced E-selectin ligand expression on activated T cells upon exposure to Ag, ligand expression on NK cells was constitutive. CHS responses were significantly lowered by orally administered 4-F-GlcNAc treatment. Although E-selectin ligand on activated T cells was suppressed, ligand expression on NK cells was insensitive to 4-F-GlcNAc treatment. These findings indicate that downregulating effector T cell E- and P-selectin ligand expression directly correlates with anti-inflammatory efficacy and provides new insight on metabolic discrepancies of E-selectin ligand biosynthesis in effector leukocytes in vivo. [Abstract]

Pacheco P, Vieira-de-Abreu A, Gomes RN, Barbosa-Lima G, Wermelinger LB, Maya-Monteiro CM, Silva AR, Bozza MT, Castro-Faria-Neto HC, Bandeira-Melo C, Bozza PT
Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 Controls Microtubule-Driven Biogenesis and Leukotriene B4-Synthesizing Function of Macrophage Lipid Bodies Elicited by Innate Immune Response.
J Immunol. 2007 Dec 15;179(12):8500-8.
Lipid bodies (also known as lipid droplets) are emerging as inflammatory organelles with roles in the innate immune response to infections and inflammatory processes. In this study, we identified MCP-1 as a key endogenous mediator of lipid body biogenesis in infection-driven inflammatory disorders and we described the cellular mechanisms and signaling pathways involved in the ability of MCP-1 to regulate the biogenesis and leukotriene B(4) (LTB(4)) synthetic function of lipid bodies. In vivo assays in MCP-1(-/-) mice revealed that endogenous MCP-1 produced during polymicrobial infection or LPS-driven inflammatory responses has a critical role on the activation of lipid body-assembling machinery, as well as on empowering enzymatically these newly formed lipid bodies with LTB(4) synthetic function within macrophages. MCP-1 triggered directly the rapid biogenesis of distinctive LTB(4)-synthesizing lipid bodies via CCR2-driven ERK- and PI3K-dependent intracellular signaling in in vitro-stimulated macrophages. Disturbance of microtubule organization by microtubule-active drugs demonstrated that MCP-1-induced lipid body biogenesis also signals through a pathway dependent on microtubular dynamics. Besides biogenic process, microtubules control LTB(4)-synthesizing function of MCP-1-elicited lipid bodies, in part by regulating the compartmentalization of key proteins, as adipose differentiation-related protein and 5-lipoxygenase. Therefore, infection-elicited MCP-1, besides its known CCR2-driven chemotactic function, appears as a key activator of lipid body biogenic and functional machineries, signaling through a microtubule-dependent manner. [Abstract]

Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, Newnham JP, Kramer BW
Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis.
J Immunol. 2007 Dec 15;179(12):8491-8499.
In a model of human chorioamnionitis, fetal sheep exposed to a single injection, but not repeated injections, of intra-amniotic endotoxin develop lung injury responses. We hypothesized that repeated exposure to intra-amniotic endotoxin induces endotoxin tolerance. Fetal sheep were given intra-amniotic injections of saline (control) or Escherichia coli LPS O55:B5 (10 mg) either 2 days (2-day group, single exposure), 7 days (7-day group, single exposure), or 2 plus 7 days (2- and 7-day repeat exposure) before preterm delivery at 124 days gestation (term = 150 days). Endotoxin responses were assessed in vivo in the lung and liver, and in vitro in monocytes from the blood and the lung. Compared with the single 2-day LPS exposure group, the (2 plus 7 days) repeat LPS-exposed lambs had: 1) decreased lung neutrophil and monocyte inducible NO synthase (NOSII) expression, and 2) decreased lung cytokine and liver serum amyloid A3 mRNA expression. In the lung, serum amyloid A3 mRNA expression decreased in the airway epithelial cells but not in the lung inflammatory cells. Unlike the single 7-day LPS exposure group, peripheral blood and lung monocytes from the repeat-LPS group did not increase IL-6 secretion or hydrogen peroxide production in response to in vitro LPS. Compared with controls, TLR4 expression did not change but IL-1R-associated kinase M expression increased in the monocytes from repeat LPS-exposed lambs. These results are consistent with the novel finding of endotoxin tolerance in preterm fetal lungs exposed to intra-amniotic LPS. The findings have implications for preterm infants exposed to chorioamnionitis for both responses to lung injury and postnatal nosocomial infections. [Abstract]

Lakshmanan U, Porter AG
Caspase-4 Interacts with TNF Receptor-Associated Factor 6 and Mediates Lipopolysaccharide-Induced NF-{kappa}B-Dependent Production of IL-8 and CC Chemokine Ligand 4 (Macrophage-Inflammatory Protein-1 ).
J Immunol. 2007 Dec 15;179(12):8480-90.
Human caspase-4 does not have a corresponding mouse ortholog. Caspase-4 falls within the class of "inflammatory caspases," being homologous with human caspases 1 and 5 and mouse caspases 1, 11, and 12. To address the function of caspase-4, we generated caspase-4-deficient human THP1 monocytic cell lines which exhibited substantially reduced LPS-induced secretion of several chemokines and cytokines, including IL-8 (CXCL8), CCL4 (macrophage-inflammatory protein-1beta), CCL20 (macrophage-inflammatory protein-3alpha), and IL-1beta. The LPS-induced expression of the mRNAs encoding these cytokines was correspondingly reduced in the caspase-4-deficient clones. Because a specific NF-kappaB inhibitor blocked LPS-induced IL-8 and CCL4 mRNA expression as well as IL-8 and CCL4 secretion in THP1 cells, we investigated the role of caspase-4 in NF-kappaB signaling. LPS-induced NF-kappaB nuclear translocation and activation were inhibited in all caspase-4-deficient clones. LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4. Mutation of this site in caspase-4 resulted in the loss of the TRAF6-caspase-4 interaction. Similar TRAF6-binding motifs are known to be functionally important for TRAF6 interactions with other molecules including caspase-8, and for mediating NF-kappaB activation in various immune and nonimmune cell types. Our data suggest that the TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-kappaB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells. [Abstract]

Döring A, Wild M, Vestweber D, Deutsch U, Engelhardt B
E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice.
J Immunol. 2007 Dec 15;179(12):8470-9.
In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood-brain barrier (BBB) and gain access to the CNS. It is well-established that alpha(4) integrins are actively involved in leukocyte recruitment across the BBB during EAE. In contrast, the role of endothelial E- and P-selectin in this process has been a controversial issue. In this study, we demonstrate that P-selectin protein can be detected in meningeal blood vessel endothelial cells in healthy SJL and C57BL/6 mice and on rare parenchymal CNS blood vessels in C57BL/6, but not SJL, mice. During EAE, expression of P-selectin but not E-selectin was found up-regulated on inflamed CNS microvessels surrounded by inflammatory infiltrates irrespective of their meningeal or parenchymal localization with a more prominent immunostaining detected in C57BL/6 as compared with SJL mice. P-selectin immunostaining could be localized to CNS endothelial cells and to CD41-positive platelets adhering to the vessel wall. Despite the presence of P-selectin in wild-type mice, E/P-selectin-deficient SJL and C57BL/6 mice developed clinical EAE indistinguishable from wild-type mice. Absence of E- and P-selectin did neither influence the activation of myelin-specific T cells nor the composition of the cellular infiltrates in the CNS during EAE. Finally, endothelial-specific tetracycline-inducible expression of E-selectin at the BBB in transgenic C57BL/6 mice did not alter the development of EAE. Thus, E- and P-selectin are not required for leukocyte recruitment across the BBB and the development of EAE in C57BL/6 and in SJL mice. [Abstract]

Mohan K, Issekutz TB
Blockade of Chemokine Receptor CXCR3 Inhibits T Cell Recruitment to Inflamed Joints and Decreases the Severity of Adjuvant Arthritis.
J Immunol. 2007 Dec 15;179(12):8463-9.
T lymphocytes expressing the chemokine receptors, CCR2, CCR5, CXCR3, and CXCR6 are increased in inflamed tissues in rheumatoid arthritis. The role of CXCR3 in autoimmune arthritis induced in Lewis rats was investigated. CXCR3(+) T cells migrated 2- to 3-fold more than CXCR3(-) T cells to inflamed joints in arthritic animals. CXCR3-expressing in vivo Ag-activated T lymphoblasts and in vitro-activated lymph node cells from arthritic animals were strongly recruited to the arthritic joints, and treatment with anti-CXCR3 mAb significantly inhibited this T cell recruitment by 40-60%. Immune T cells from the spleen and lymph nodes of actively immunized arthritic donors adoptively transferred arthritis to naive rats. Treatment with anti-CXCR3 mAb delayed the onset of arthritis and significantly reduced the severity of joint inflammation with a >50% decrease in the clinical arthritis score. Blockade of CXCR3 also significantly reduced the weight loss in the arthritic animals and inhibited neutrophil accumulation in the joints by 50-60%. There was a marked reduction in the leukocyte infiltration of the synovium in the presence of CXCR3 blockade and a decrease in the loss of articular cartilage of the joints. In conclusion, CXCR3 on T cells has an essential role in T cell recruitment to inflamed joints and the development of joint inflammation in adjuvant arthritis. [Abstract]

Yoon J, Terada A, Kita H
CD66b Regulates Adhesion and Activation of Human Eosinophils.
J Immunol. 2007 Dec 15;179(12):8454-62.
Eosinophils and their products are likely important in the pathophysiology of allergic diseases, such as bronchial asthma, and in host immunity to parasitic organisms. However, the mechanisms for proinflammatory mediator release by eosinophils are poorly understood. CD66b (CEACAM8, CGM6, NCA-95) is a single chain, GPI-anchored, highly glycosylated protein belonging to the carcinoembryonic Ag supergene family. CD66b is an activation marker for human granulocytes; however, its biological functions are largely unknown in eosinophils. We found that CD66b is highly expressed on the surface of human peripheral blood eosinophils isolated from healthy individuals. Engagement of CD66b, but not CD66a, by mAb or a natural ligand, galectin-3, activated a Src kinase family molecule, hemopoietic cell kinase (Hck), and induced cellular adhesion, superoxide production, and degranulation of eosinophils. CD66b molecules were localized in lipid rafts, and disruption of lipid rafts or removal of the GPI anchor inhibited the adhesion and activation of eosinophils. Importantly, CD66b was constitutively and physically associated with a beta(2) integrin, CD11b, and cross-linking of CD66b induced a striking clustering of CD11b molecules. Thus, CD66b molecules are involved in regulating adhesion and activation of eosinophils, possibly through their localization in lipid rafts and interaction with other cell surface molecules, such as CD11b. Binding of exogenous or endogenous carbohydrate ligands(s) to CD66b may be important in the release of proinflammatory mediators by human eosinophils. [Abstract]

Gaur U, Roberts SC, Dalvi RP, Corraliza I, Ullman B, Wilson ME
An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis.
J Immunol. 2007 Dec 15;179(12):8446-53.
Classical activation of macrophages infected with Leishmania species results in expression and activation of inducible NO synthase (iNOS) leading to intracellular parasite killing. Macrophages can contrastingly undergo alternative activation with increased arginase activity, metabolism of arginine along the polyamine pathway, and consequent parasite survival. An active role for parasite-encoded arginase in host microbicidal responses has not previously been documented. To test the hypothesis that parasite-encoded arginase can influence macrophage responses to intracellular Leishmania, a comparative genetic approach featuring arginase-deficient mutants of L. mexicana lacking both alleles of the gene encoding arginase (Deltaarg), as well as wild-type and complemented Deltaarg controls (Deltaarg[pArg]), was implemented. The studies showed: 1) the absence of parasite arginase resulted in a significantly attenuated infection of mice (p < 0.05); 2) poorer survival of Deltaarg in mouse macrophages than controls correlated with greater NO generation; 3) the difference between Deltaarg or control intracellular survival was abrogated in iNOS-deficient macrophages, suggesting iNOS activity was responsible for increased Deltaarg killing; 4) consistently, immunohistochemistry showed enhanced nitrotyrosine modifications in tissues of mice infected with Deltaarg compared with control parasites. Furthermore, 5) in the face of decreased parasite survival, lymph node cells draining cutaneous lesions of Deltaarg parasites produced more IFN-gamma and less IL-4 and IL-10 than controls. These data intimate that parasite-encoded arginase of Leishmania mexicana subverts macrophage microbicidal activity by diverting arginine away from iNOS. [Abstract]

Müller V, Viemann D, Schmidt M, Endres N, Ludwig S, Leverkus M, Roth J, Goebeler M
Candida albicans Triggers Activation of Distinct Signaling Pathways to Establish a Proinflammatory Gene Expression Program in Primary Human Endothelial Cells.
J Immunol. 2007 Dec 15;179(12):8435-45.
Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-kappaB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-kappaB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IkappaB kinase-2/NF-kappaB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen. [Abstract]

Yu Y, Yu Y, Huang H, Feng K, Pan M, Yuan S, Huang S, Wu T, Guo L, Dong M, Chen S, Xu A
A Short-Form C-Type Lectin from Amphioxus Acts as a Direct Microbial Killing Protein via Interaction with Peptidoglycan and Glucan.
J Immunol. 2007 Dec 15;179(12):8425-8434.
To investigate the evolution and immune function of C-type lectin in amphioxus, the primitive representative of the chordate phylum, we identified three C-type lectins consisting solely of a carbohydrate recognition domain and N-terminal signal peptide and found that they had distinct express patterns in special tissues and immune response to stimulations analyzed by quantitative real-time PCR. We characterized the biochemical and biological properties of AmphiCTL1, which was dramatically up-regulated in amphioxus challenged with Staphylococcus aureus, Saccharomyces cerevisiae, and zymosan. Immunohistochemistry demonstrated that the localization of AmphiCTL1 protein was exclusively detected in the inner folding tissues of the hepatic diverticulum. Recombinant AmphiCTL1 was characterized as a typical Ca(2+)-dependent carbohydrate-binding protein possessing hemagglutinating activity, preferentially bound to all examined four Gram-positive bacteria and two yeast strains, but had little binding activity toward four Gram-negative bacteria we tested. It aggregated S. aureus and S. cerevisiae in a Ca(2+)-dependent manner and specifically bound to insoluble peptidoglycan and glucan, but not to LPS, lipoteichoic acid, and mannan. Calcium increased the intensity of the interaction between AmphiCTL1 and those components, but was not essential. This lectin directly killed S. aureus and S. cerevisiae in a Ca(2+)-independent fashion, and its binding to microorganism cell wall polysaccharides such as peptidoglycan and glucan preceded microbial killing activity. These findings suggested that AmphiCTL1 acted as a direct microbial killing C-type lectin through binding microbial targets via interaction with peptidoglycan and glucan. Thus, AmphiCTL1 may be an evolutionarily primitive form of antimicrobial protein involved in lectin-mediated innate immunity. [Abstract]

Ryan AA, Wozniak TM, Shklovskaya E, O'Donnell MA, Fazekas de St Groth B, Britton WJ, Triccas JA
Improved Protection against Disseminated Tuberculosis by Mycobacterium bovis Bacillus Calmette-Guerin Secreting Murine GM-CSF Is Associated with Expansion and Activation of APCs.
J Immunol. 2007 Dec 15;179(12):8418-24.
Modulating the host-immune response by the use of recombinant vaccines is a potential strategy to improve protection against microbial pathogens. In this study, we sought to determine whether secretion of murine GM-CSF by the bacillus Calmette-Guérin (BCG) vaccine influenced protective immunity against Mycobacterium tuberculosis. BCG-derived GM-CSF stimulated the in vitro generation of functional APCs from murine bone marrow precursors, as demonstrated by the infection-induced secretion of IL-12 by differentiated APCs, and the ability of these cells to present Ag to mycobacterium-specific T cells. Mice vaccinated with BCG-secreting murine GM-CSF (BCG:GM-CSF) showed increased numbers of CD11c(+)MHCII(+) and CD11c(-)CD11b(+)F480(+) cells compared with those vaccinated with control BCG, and this effect was most apparent in the draining lymph nodes at 7 and 14 days postvaccination. Vaccination with BCG:GM-CSF also resulted in enhanced expression of costimulatory molecules on migratory dendritic cells in the draining lymph nodes. The increased APC number was associated with an increase in the frequency of anti-mycobacterial IFN-gamma-secreting T cells generated after BCG:GM-CSF vaccination compared with vaccination with control BCG, and this effect was sustained up to 17 wk in the spleens of immunized mice. Vaccination with BCG:GM-CSF resulted in an approximately 10-fold increase in protection against disseminated M. tuberculosis infection compared with control BCG. This study demonstrates the potential of BCG-secreting immunostimulatory molecules as vaccines to protect against tuberculosis and suggests BCG:GM-CSF merits further appraisal as a candidate to control M. tuberculosis infection in humans. [Abstract]

Heidema J, Lukens MV, van Maren WW, van Dijk ME, Otten HG, van Vught AJ, van der Werff DB, van Gestel SJ, Semple MG, Smyth RL, Kimpen JL, van Bleek GM
CD8+ T Cell Responses in Bronchoalveolar Lavage Fluid and Peripheral Blood Mononuclear Cells of Infants with Severe Primary Respiratory Syncytial Virus Infections.
J Immunol. 2007 Dec 15;179(12):8410-8417.
A protective role for CD8(+) T cells during viral infections is generally accepted, but little is known about how CD8(+) T cell responses develop during primary infections in infants, their efficacy, and how memory is established after viral clearance. We studied CD8(+) T cell responses in bronchoalveolar lavage (BAL) samples and blood of infants with a severe primary respiratory syncytial virus (RSV) infection. RSV-specific CD8(+) T cells with an activated effector cell phenotype: CD27(+)CD28(+)CD45RO(+)CCR7(-)CD38(+)HLA-DR(+)Granzyme B(+)CD127(-) could be identified in BAL and blood. A high proportion of these CD8(+) T cells proliferated and functionally responded upon in vitro stimulation with RSV Ag. Thus, despite the very young age of the patients, a robust systemic virus-specific CD8(+) T cell response was elicited against a localized respiratory infection. RSV-specific T cell numbers as well as the total number of activated effector type CD8(+) T cells peaked in blood around day 9-12 after the onset of primary symptoms, i.e., at the time of recovery. The lack of a correlation between RSV-specific T cell numbers and parameters of disease severity make a prominent role in immune pathology unlikely, in contrast the T cells might be involved in the recovery process. [Abstract]

Arjona A, Ledizet M, Anthony K, Bonafé N, Modis Y, Town T, Fikrig E
West Nile Virus Envelope Protein Inhibits dsRNA-Induced Innate Immune Responses.
J Immunol. 2007 Dec 15;179(12):8403-9.
The immune response against viral infection relies on the early production of cytokines that induce an antiviral state and trigger the activation of immune cells. This response is initiated by the recognition of virus-associated molecular patterns such as dsRNA, a viral replication intermediate recognized by TLR3 and certain RNA helicases. Infection with West Nile virus (WNV) can lead to lethal encephalitis in susceptible individuals and constitutes an emerging health threat. In this study, we report that WNV envelope protein (WNV-E) specifically blocks the production of antiviral and proinflammatory cytokines induced by dsRNA in murine macrophages. This immunosuppressive effect was not dependent on TLR3 or its adaptor molecule Trif. Instead, our experiments show that WNV-E acts at the level of receptor-interacting protein 1. Our results also indicate that WNV-E requires a certain glycosylation pattern, specifically that of dipteran cells, to inhibit dsRNA-induced cytokine production. In conclusion, these data show that the major structural protein of WNV impairs the innate immune response and suggest that WNV exploits differential vector/host E glycosylation profiles to evade antiviral mechanisms. [Abstract]

Kayhan B, Yager EJ, Lanzer K, Cookenham T, Jia Q, Wu TT, Woodland DL, Sun R, Blackman MA
A Replication-Deficient Murine {gamma}-Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity.
J Immunol. 2007 Dec 15;179(12):8392-402.
The human gamma-herpesviruses, EBV and Kaposi's sarcoma-associated herpesvirus, are widely disseminated and are associated with the onset of a variety of malignancies. Thus, the development of prophylactic and therapeutic vaccination strategies is an important goal. The experimental mouse gamma-herpesvirus, gammaHV68 (or MHV-68), has provided an in vivo model for studying immune control of these persistent viruses. In the current studies, we have examined infectivity, immunogenicity, and protective efficacy following infection with a replication-deficient gammaHV68 blocked in late viral gene expression, ORF31STOP. The data show that ORF31STOP was able to latently infect B cells. However, the anatomical site and persistence of the infection depended on the route of inoculation, implicating a role for viral replication in viral spread but not the infectivity per se. Furthermore, i.p. infection with ORF31STOP elicited strong cellular immunity but a non-neutralizing Ab response. In contrast, intranasal infection was poorly immunogenic. Consistent with this, mice infected i.p. had enhanced control of both the lytic and latent viral loads following challenge with wild-type gammaHV68, whereas intranasal infected mice were not protected. These data provide important insight into mechanisms of infection and protective immunity for the gamma-herpesviruses and demonstrate the utility of replication-deficient mutant viruses in direct testing of "proof of principal" vaccination strategies. [Abstract]

Arias MA, Jaramillo G, López YP, Mejía N, Mejía C, Pantoja AE, Shattock RJ, García LF, Griffin GE
Mycobacterium tuberculosis Antigens Specifically Modulate CCR2 and MCP-1/CCL2 on Lymphoid Cells from Human Pulmonary Hilar Lymph Nodes.
J Immunol. 2007 Dec 15;179(12):8381-91.
Macrophages and dendritic cells are involved in the immune response to Mycobacterium tuberculosis (Mtb). Such a response, although extensively studied using animal models and cells from human blood, has not been characterized in cells from pulmonary hilar lymph nodes (PHLN). We characterized populations of myeloid APC from PHLN and determined their expression of CCR2, CCR5, CCR7, CD40, CD54, CD80, and CD86 as well as the cytokine/chemokine microenvironment before and after purified protein derivative (PPD) and mannosilated lipoarabinomannan (ManLAM) stimulation. Results show that there are at least three APC populations in PHLN, defined as CD14(high)HLA-DR(low/-), CD14(dim)HLA-DR(dim), and CD14(-)HLA-DR(high)/dendritic cells (DC), with the largest number represented by CD14(dim)HLA-DR(dim) cells (where dim indicates intermediate levels). CD14(-)HLA-DR(high)/DC expressed higher levels of costimulatory molecules and lower levels of CCR2 and CCR5, but all cell populations showed similar CCR7 levels. PPD and ManLAM specifically down-regulated CCR2 expression but not that of CCR5 and CCR7, and such down-regulation was observed on all APC populations. Mtb Ag did not affect the expression of costimulatory molecules. PPD but not ManLAM specifically induced MCP-1/CCL2 production, which was likely associated with the induction of IFN-gamma because this cytokine was highly induced by PPD. We characterized, for the first time, different APC from human PHLN and show that Mtb Ag exert fine and specific regulation of molecules closely associated with the immune response to Mtb infection. Because knowledge of this response in secondary lymphoid tissues is still poorly understood in humans, such studies are necessary and important for a better understanding of lymphoid cell microenvironment and migrating capacities and their role in the immunopathogenesis of tuberculosis. [Abstract]

Zhang G, Russell-Lodrigue KE, Andoh M, Zhang Y, Hendrix LR, Samuel JE
Mechanisms of Vaccine-Induced Protective Immunity against Coxiella burnetii Infection in BALB/c Mice.
J Immunol. 2007 Dec 15;179(12):8372-80.
To elucidate the mechanisms of vaccine-induced protective immunity against Coxiella burnetii infection, we compared the protective efficacy and immunogenicity between formalin-inactivated phase I vaccine (PI-V) and phase II vaccine (PII-V) in BALB/c mice. PI-V generated significant protection while PII-V did not confer measurable protection. Analysis of cytokine and subclass Ab responses indicated that both PI-V and PII-V were able to induce a Th1-dominant immune response but did not identify the component of host response that distinguished their ability to induce protective immunity. Interestingly, immunoblot analysis identified a difference between PI-V and PII-V vaccinates in antigenic recognition by specific Ab isotypes. The observation that PI-LPS elicited significant protection but PII-LPS did not confer measurable protection suggests PI-LPS may play a key role in PI-V-induced protection. Adoptive transfer of either immune sera or splenocytes mediated significant protection in naive BALB/c mice, supporting the notion that both humoral and cellular immunity are important for development of protective immunity. However, the evidence that immune sera and B cells were unable to control infection while T cells conferred significant protection in SCID mice supports the hypothesis that T cell-mediated immunity is critical for host defense against C. burnetii infection. This report presents novel evidence to highlight the importance of PI-LPS and Abs in protective immunity and has important implications for the design of new generation vaccines against Q fever. [Abstract]

Ellis MK, Zhao ZZ, Chen HG, Montgomery GW, Li YS, McManus DP
Analysis of the 5q31 33 Locus Shows an Association between Single Nucleotide Polymorphism Variants in the IL-5 Gene and Symptomatic Infection with the Human Blood Fluke, Schistosoma japonicum.
J Immunol. 2007 Dec 15;179(12):8366-71.
Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously identified a genetic locus determining infection intensity with the African species, Schistosoma mansoni, in the 5q31-33 region of the human genome that is known to contain the Th2 immune response cluster, including the genes encoding the IL-4, IL-5, and IL-13 cytokines. These cytokines are key players in inflammatory immune responses and have previously been implicated in human susceptibility to infection with the Asian species, S. japonicum. In a nested case control study, we genotyped 30 HapMap tagging single nucleotide polymorphisms (SNPs) across these three genes in 159 individuals identified as putatively susceptible to reinfection with S. japonicum and in 133 putatively resistant individuals. A third group comprising 113 individuals demonstrating symptomatic infection was also included. The results provided no significant association at a global level between reinfection predisposition and any of the individual SNPs or haplotype blocks. However, two tagging SNPs in IL-5 demonstrated globally significant association with susceptibility to symptomatic infection. They were in strong linkage disequilibrium with each other and were found to belong to the same haplotype block that also provided a significant association after permutation testing. This haplotype was located in the 3'-untranslated region of IL-5, suggesting that variants in this region of IL-5 may modulate the immune response in these individuals with symptomatic infection. [Abstract]

Persson EK, Agnarson AM, Lambert H, Hitziger N, Yagita H, Chambers BJ, Barragan A, Grandien A
Death Receptor Ligation or Exposure to Perforin Trigger Rapid Egress of the Intracellular Parasite Toxoplasma gondii.
J Immunol. 2007 Dec 15;179(12):8357-65.
The obligate intracellular parasite Toxoplasma gondii chronically infects up to one-third of the global population, can result in severe disease in immunocompromised individuals, and can be teratogenic. In this study, we demonstrate that death receptor ligation in T. gondii-infected cells leads to rapid egress of infectious parasites and lytic necrosis of the host cell, an active process mediated through the release of intracellular calcium as a consequence of caspase activation early in the apoptotic cascade. Upon acting on infected cells via death receptor- or perforin-dependent pathways, T cells induce rapid egress of infectious parasites able to infect surrounding cells, including the Ag-specific effector cells. [Abstract]

Canetti C, Serezani CH, Atrasz RG, White ES, Aronoff DM, Peters-Golden M
Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of Fc{gamma}R Phagocytosis by Prostaglandin E2 in Alveolar Macrophages.
J Immunol. 2007 Dec 15;179(12):8350-6.
PGE(2) has important inhibitory effects on the macrophage host defense functions of phagocytosis and killing, yet the molecular mechanisms involved remain to be fully elucidated. PGE(2) causes an elevation of cAMP in alveolar macrophages (AMs), which in turn activates the cAMP effector targets, protein kinase A and the exchange protein activated by cAMP (Epac)-1. We now report that FcgammaR-induced PI3K/Akt and ERK-1/2 activation are inhibited by PGE(2) in AMs. By specifically inhibiting the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in AMs, we attenuated the inhibitory effects of both PGE(2) and a specific Epac-1 agonist (8-pCPT-2'-O-Me-cAMP) on FcgammaR-mediated phagocytosis and Akt/ERK-1/2 activation; PTEN inhibition also decreased PGE(2)-induced suppression of bacterial killing by AMs. Moreover, PGE(2) and the Epac-1 agonist induced an increase in PTEN lipid phosphatase activity, and this was associated with decreased tyrosine phosphorylation on PTEN-a mechanism known to regulate PTEN activity. Using a pharmacological approach, we demonstrated a role for Src homology 2-containing protein tyrosine phosphatase-1 in the PGE(2)-induced tyrosine dephosphorylation of PTEN. Collectively, these data reveal that PGE(2), via Epac-1 activation, enhances SHP-1 activity, resulting in increased PTEN activity. We suggest that this mechanism contributes to the ability of PGE(2) to inhibit PI3K-dependent innate immune signaling in primary macrophages. [Abstract]

Hunter K, Rainbow D, Plagnol V, Todd JA, Peterson LB, Wicker LS
Interactions between Idd5.1/Ctla4 and Other Type 1 Diabetes Genes.
J Immunol. 2007 Dec 15;179(12):8341-9.
Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type 1 diabetes (T1D) in the NOD mouse are on chromosome 1. Idd5.1 is likely accounted for by a synonymous single nucleotide polymorphism in exon 2 of Ctla4: the B10-derived T1D-resistant allele increases the expression of the ligand-independent isoform of CTLA-4 (liCTLA-4), a molecule that mediates negative signaling in T cells. Idd5.2 is probably Nramp1 (Slc11a1), which encodes a phagosomal membrane protein that is a metal efflux pump and is important for host defense and Ag presentation. In this study, two additional loci, Idd5.3 and Idd5.4, have been defined to 3.553 and 78 Mb regions, respectively, on linked regions of chromosome 1. The most striking findings, however, concern the evidence we have obtained for strong interactions between these four disease loci that help explain the association of human CTLA4 with T1D. In the presence of a susceptibility allele at Idd5.4, the CTLA-4 resistance allele causes an 80% reduction in T1D, whereas in the presence of a protective allele at Idd5.4, the effects of the resistance allele at Ctla4 are modest or, as in the case in which resistance alleles at Idd5.2 and Idd5.3 are present, completely masked. This masking of CTLA-4 alleles by different genetic backgrounds provides an explanation for our observation that the human CTLA-4 gene is only associated with T1D in the subgroup of human T1D patients with anti-thyroid autoimmunity. [Abstract]

Simkus C, Anand P, Bhattacharyya A, Jones JM
Biochemical and Folding Defects in a RAG1 Variant Associated with Omenn Syndrome.
J Immunol. 2007 Dec 15;179(12):8332-40.
The RAG1 and RAG2 proteins are required to assemble mature Ag receptor genes in developing lymphocytes. Hypomorphic mutations in the gene encoding RAG1 are associated with Omenn syndrome, a primary immunodeficiency. We explored the biochemical defects resulting from a mutation identified in an Omenn syndrome patient which generates an amino acid substitution in the RAG1 RING finger/ubiquitin ligase domain (C325Y in murine RAG1) as well as an adjacent substitution (P326G). RAG1 C325Y demonstrated a 50-fold reduction in recombination activity in cultured pro-B cells despite the fact that its expression and localization to the nucleus were similar to the wild-type protein. The C325Y substitution severely abrogated ubiquitin ligase activity of the purified RAG1 RING finger domain, and the tertiary structure of the domain was altered. The P326G substitution also abrogated ubiquitin ligase activity but had a less severe effect on protein folding. RAG1 P326G also demonstrated a recombination impairment that was most pronounced when RAG1 levels were limiting. Thus, a correctly folded RAG1 RING finger domain is required for normal V(D)J recombination, and RAG1 ubiquitin ligase activity can contribute when the protein is present at relatively low levels. [Abstract]

Li Y, Yan J, De P, Chang HC, Yamauchi A, Christopherson KW, Paranavitana NC, Peng X, Kim C, Munugulavadla V, Kapur R, Chen H, Shou W, Stone JC, Kaplan MH, Dinauer MC, Durden DL, Quilliam LA
Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related rap1a and 1b proteins.
J Immunol. 2007 Dec 15;179(12):8322-31.
The Ras-related GTPases Rap1a and 1b have been implicated in multiple biological events including cell adhesion, free radical production, and cancer. To gain a better understanding of Rap1 function in mammalian physiology, we deleted the Rap1a gene. Although loss of Rap1a expression did not initially affect mouse size or viability, upon backcross into C57BL/6J mice some Rap1a(-/-) embryos died in utero. T cell, B cell, or myeloid cell development was not disrupted in Rap1a (-/-) mice. However, macrophages from Rap1a null mice exhibited increased haptotaxis on fibronectin and vitronectin matrices that correlated with decreased adhesion. Chemotaxis of lymphoid and myeloid cells in response to CXCL12 or CCL21 was significantly reduced. In contrast, an increase in FcR-mediated phagocytosis was observed. Because Rap1a was previously copurified with the human neutrophil NADPH oxidase, we addressed whether GTPase loss affected superoxide production. Neutrophils from Rap1a(-/-) mice had reduced fMLP-stimulated superoxide production as well as a weaker initial response to phorbol ester. These results suggest that, despite 95% amino acid sequence identity, similar intracellular distribution, and broad tissue distribution, Rap1a and 1b are not functionally redundant but rather differentially regulate certain cellular events. [Abstract]

Radcliffe JN, Roddick JS, Stevenson FK, Thirdborough SM
Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development.
J Immunol. 2007 Dec 15;179(12):8313-21.
After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8(+) T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8(+) T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8(+) T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8(+) T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8(+) T cells, these expanded less ( approximately 4-fold) than those induced by transient Ag expression ( approximately 35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8(+) T cell vaccines will be those that deliver a short burst of Ag. [Abstract]

Murapa P, Gandhapudi S, Skaggs HS, Sarge KD, Woodward JG
Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1).
J Immunol. 2007 Dec 15;179(12):8305-12.
Heat shock factor-1 (HSF1) is a transcription factor that serves as the major temperature-inducible sensor for eukaryotic cells. In most cell types, HSF1 becomes activated to the DNA binding form at 42 degrees C and mediates the classical heat shock response, protecting the cells from subsequent lethal temperatures. We have recently demonstrated that HSF1 is activated at a lower temperature in T lymphocytes than in most other cell types (39 degrees C vs 42 degrees C), within the physiological range of fever. In this study, we show that T cell activation at fever temperatures not only activates HSF1 but induces the up-regulation of the HSF1 protein and the HSF1-regulated protein, HSP70i. T cells from HSF1 knockout mice proliferate normally under optimal conditions but are impaired in proliferation at physiological fever temperatures and low CO(2) concentrations, conditions that do not impair wild-type T cells. This defect in proliferation appears to be mediated by a block in the G(1)/S transition of the cell cycle and is independent of HSP70. Elevated temperature and low CO(2) concentrations resulted in a dramatic reduction of the intracellular reactive oxygen species (ROS) levels in both normal and knockout T cells. Wild-type T cells were able to restore ROS levels to normal within 5 h, whereas HSF1(-/-) T cells were not. These results suggest that the proliferation defect seen in T cells from HSF1(-/-) mice at fever temperatures was because of dysregulated ROS levels and that HSF1 is important in maintaining ROS homeostasis and cell cycle progression under the stressful conditions encountered during fever. [Abstract]

Recent Articles in Immunological Reviews

Krieg AM, Vollmer J
Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity.
Immunol Rev. 2007 Dec;220(1):251-69.
Toll-like receptors (TLRs) detect infections by highly conserved components of pathogens that are either not present in our own cells or are normally sequestered in cellular compartments that are inaccessible to the TLRs. Most TLRs are expressed on the cell surface, where they have been shown to detect pathogen-expressed molecules such as lipopolysaccharides and lipopeptides. A subset of TLRs, including TLR3, TLR7, TLR8, and TLR9, are expressed intracellularly within one or more endosomal compartments and detect nucleic acids. Because pathogen and host nucleic acids have very similar structures, these endosomal TLRs may face an extra challenge to induce anti-pathogen immune responses while avoiding the induction of autoimmune diseases. With the rapid growth in understanding of the biology of the TLRs has come an increasing awareness of their effects on autoimmunity, several aspects of which are the focus of this review. First, recent studies have revealed an inappropriate activation of TLR7, TLR8, and TLR9 in systemic lupus erythematosus and several other autoimmune diseases. Secondly, the potential for therapeutic development of TLR antagonists is considered. Finally, with the rapid progress in the development of therapeutic agonists for the TLRs, there is accompanying attention to the theoretical possibility that such therapy may induce autoimmunity or autoimmune diseases. [Abstract]

Nagata S
Autoimmune diseases caused by defects in clearing dead cells and nuclei expelled from erythroid precursors.
Immunol Rev. 2007 Dec;220(1):237-50.
Apoptotic cells are recognized and subsequently engulfed by macrophages and immature dendritic cells. The engulfed dead cells are transported to the lysosomes of macrophages, and their components are degraded into amino acids and nucleotides for reuse. In mammals, macrophages also engulf nuclei expelled from erythroid precursors in the final stage of definitive erythropoiesis. Failure to swiftly engulf dead cells at the germinal centers of lymphoid organs causes systemic lupus erythematosus-type autoimmune diseases. In contrast, failure to efficiently degrade the DNA of dead cells or erythroid cell nuclei activates innate immunity, causing lethal anemia in the fetus and chronic arthritis in adults. [Abstract]

Zhang SY, Jouanguy E, Sancho-Shimizu V, von Bernuth H, Yang K, Abel L, Picard C, Puel A, Casanova JL
Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses.
Immunol Rev. 2007 Dec;220(1):225-236.
Five of the 10 human Toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)-alpha, IFN-beta, and IFN-lambda, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly important ways for antiviral immunity: they can be activated by nucleic acid agonists mimicking compounds produced during the viral cycle, and they are typically present within the cell, along the endocytic pathway, where they sense viral products in the intraluminal space. Investigations in mice have demonstrated that the TLR7/9-IFN and TLR3-IFN pathways are different and critical for protective immunity to various experimental viral infections. Investigations in humans with interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency (unresponsive to TLR7, TLR8, and TLR9), UNC-93B deficiency (unresponsive to TLR3, TLR7, TLR8, and TLR9), and TLR3 deficiency have recently shed light on the role of these two pathways in antiviral immunity in natural conditions. UNC-93B- and TLR3-deficient patients appear to be specifically prone to herpes simplex virus 1 (HSV-1) encephalitis, although clinical penetrance is incomplete, whereas IRAK-4-deficient patients appear to be normally resistant to most viruses, including HSV-1. These experiments of nature suggest that the TLR7-, TLR8-, and TLR9-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is largely redundant in human antiviral immunity, whereas the TLR3-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is critical for primary immunity to HSV-1 in the central nervous system in children but redundant for immunity to most other viral infections. [Abstract]

Takeuchi O, Akira S
Recognition of viruses by innate immunity.
Immunol Rev. 2007 Dec;220(1):214-24.
The innate immune system plays critical roles in recognizing viral infections and evoking initial anti-viral responses. Nucleotides from RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) and Toll-like receptors (TLRs), and the recognition triggers signaling cascades that induce anti-viral mediators such as type I interferons (IFNs) and pro-inflammatory cytokines. The RLH signaling pathways play essential roles in the recognition of RNA viruses in various cells, with the exception of plasmacytoid dendritic cells (pDCs). However, TLRs are important for the production of type I IFNs in pDCs but not in other cell types. The contributions of RLHs and TLRs to the production of type I IFNs in response to RNA viruses vary depending on the route of infection. Specifically, local infections induce IFNs through RLHs but not TLRs, whereas systemic infections strongly stimulate TLRs in pDCs. In this review, we discuss recent advances toward clarifying the signaling pathways activated by RLHs and TLRs. [Abstract]

Wan YY, Flavell RA
'Yin-Yang' functions of transforming growth factor-beta and T regulatory cells in immune regulation.
Immunol Rev. 2007 Dec;220(1):199-213.
Transforming growth factor-beta (TGF-beta) and forkhead box p3-expressing T-regulatory (Treg) cells are critical in maintaining self-tolerance and immune homeostasis. The immune suppressive functions of TGF-beta and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles of TGF-beta and Treg cells in shaping the immune system and the inflammatory responses. This review discusses our and other's efforts in understanding the negative (Yin) as well as the positive (Yang) roles for TGF-beta and Treg cells in immune regulation. [Abstract]

Fujii S, Shimizu K, Hemmi H, Steinman RM
Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity.
Immunol Rev. 2007 Dec;220(1):183-98.
The observation that the glycolipid alpha-galactosylceramide (alpha-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. alpha-GalCer is presented on CD1d to the invariant NKT receptor, leading to interleukin-12 (IL-12) production by dendritic cells (DCs) and to NK cell activation. We review our research on the tumor-protective properties of alpha-GalCer, particularly the major role played by DCs. We compared administration of alpha-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-gamma (IFN-gamma) production by NKT cells and better protection against B16 melanoma. Human alpha-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. alpha-GalCer-activated NKT cells were then found to induce DC maturation in vivo. The maturing DCs produced IL-12, upregulated co-stimulatory molecules, and induced adaptive immunity to captured cellular antigens, including prolonged, combined CD4(+)/CD8(+) T-cell immunity to dying tumor cells. Surprisingly, co-stimulator-poor tumor cells, if directly loaded with alpha-GalCer ('tumor/Gal') and injected intravenously, also induced strong NKT- and NK-cell responses. The latter killed the tumor/Gal, which were subsequently cross presented by CD1d on DCs to elicit DC maturation and prolonged adaptive T-cell immunity, which lasted 6-12 months. These findings help explain tumor protection via alpha-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers. [Abstract]

Grégoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T
The trafficking of natural killer cells.
Immunol Rev. 2007 Dec;220(1):169-82.
Natural killer (NK) cells are large granular lymphocytes of the innate immune system that participate in the early control of microbial infections and cancer. NK cells can induce the death of autologous cells undergoing various forms of stress, recognizing and providing non-microbial 'danger' signals to the immune system. NK cells are widely distributed in lymphoid and non-lymphoid organs. NK cell precursors originate from the bone marrow and go through a complex maturation process that leads to the acquisition of their effector functions, to changes in their expression of integrins and chemotactic receptors, and to their redistribution from the bone marrow and lymph nodes to blood, spleen, liver, and lung. Here, we describe the tissue localization of NK cells, using NKp46 as an NK cell marker, and review the current knowledge on the mechanisms that govern their trafficking in humans and in mice. [Abstract]

Cronin SJ, Penninger JM
From T-cell activation signals to signaling control of anti-cancer immunity.
Immunol Rev. 2007 Dec;220(1):151-68.
The activation of resting T cells is crucial to most immune processes. Recognition of foreign antigen by T-cell receptors has to be correctly translated into signal transduction events necessary for the induction of an effective immune response. In this review, we discuss the essential signals, molecules, and processes necessary to achieve full T-cell activation. In addition to describing these key biological events, we also discuss how T-cell receptor signaling may be harnessed to yield new therapeutic targets for a next generation of anti-cancer drugs. [Abstract]

Palucka AK, Ueno H, Fay JW, Banchereau J
Taming cancer by inducing immunity via dendritic cells.
Immunol Rev. 2007 Dec;220(1):129-50.
Immunotherapy seeks to mobilize a patient's immune system for therapeutic benefit. It can be passive, i.e. transfer of immune effector cells (T cells) or proteins (antibodies), or active, i.e. vaccination. In cancer, passive immunotherapy can lead to some objective clinical responses, thus demonstrating that the immune system can reject tumors. However, passive immunotherapy is not expected to yield long-lived memory T cells that might control tumor outgrowth. Active immunotherapy with dendritic cell (DC)-based vaccines has the potential to induce both tumor-specific effector and memory T cells. Early clinical trials testing vaccination with ex vivo-generated DCs pulsed with tumor antigens provide a proof-of-principle that therapeutic immunity can be elicited. Yet, there is a need to improve their efficacy. The next generation of DC vaccines is expected to generate large numbers of high-avidity effector CD8(+) T cells and to overcome regulatory T cells. Therapeutic vaccination protocols will combine improved ex vivo DC vaccines with therapies that offset the suppressive environment established by tumors. [Abstract]

Beutler B
Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease.
Immunol Rev. 2007 Dec;220(1):113-28.
Microbe recognition based on a small collection of germline-encoded receptors carries a hidden liability: the possibility that mutational changes in the proteome will lead to self-recognition. The risk of self-recognition is enhanced, because innate immune receptors display low specificity, as they are driven to accommodate heterogeneous signature molecules found in the microbial world. The proteome structure is globally constrained by the innate immune sensing apparatus to satisfy a proscription against self-reactivity. But accidents happen, and here it is proposed that mutations creating neo-ligands for innate immune receptors are the proximal cause of sterile inflammatory diseases, which in turn embody the selective pressure that constrains the proteome. Such mutations are predictably dominant and may occur in the germline and also in somatic cells (e.g. in lymphocytes), causing inflammatory effects upon clonal expansion. They may also account for the inflammatory character of selected neoplastic diseases. The neo-ligand hypothesis accounts for the heritability, ambiguous linkage characteristics, phenotypic heterogeneity, and natural history of diverse forms of sterile inflammation. It explains sterile inflammatory diseases as conditions in which aberrant immune signaling is caused by proteome encroachment upon the ligand-recognition space over which the innate immune system stands guard. [Abstract]

Willimsky G, Blankenstein T
The adaptive immune response to sporadic cancer.
Immunol Rev. 2007 Dec;220(1):102-12.
Most of the current experimental cancer models do not reflect the pathophysiology of real-life cancer. Cancer usually occurs sporadically and is clonal in origin. Between tumor initiation and progression, clinically unapparent pre-malignant cells may persist for years or decades in humans. Recently, mouse models of sporadic cancer have been developed. The mouse germ-line can be engineered with high precision so that defined genes can be switched on and off in the adult organism in a targeted manner. Analysis of the immune response against sporadic tumors requires the knowledge of a tumor antigen. Ideally, a silent oncogene, for which the mice are not tolerant, is stochastically activated in individual cells. This approach offers the opportunity to analyze the adaptive immune response throughout the long process of malignant transformation and most closely resembles cancer in humans. In such a model with the highly immunogenic SV40 large T antigen as a dormant oncogene, we discovered that sporadic cancer is recognized by the adaptive immune system at the pre-malignant stage, concomitant with the induction of tumor antigen-specific tolerance. These results demonstrated that even highly immunogenic sporadic tumors are unable to induce functional cytotoxic T lymphocytes. Based on this model, we conclude that immunosurveillance plays little or no role against sporadic cancer and that tumors must not escape immune recognition or destruction. [Abstract]

Stagg J, Johnstone RW, Smyth MJ
From cancer immunosurveillance to cancer immunotherapy.
Immunol Rev. 2007 Dec;220(1):82-101.
In response to oncogenic threats, tumor suppressor mechanisms that halt cell-cycle progression can stimulate immune-mediated destruction of pre-malignant and malignant cells. Accordingly, defining the molecular interactions between tumor suppressor pathways and cancer immunity may be instrumental in the development of novel cancer therapies. We here discuss the immunological consequences of cellular senescence and apoptosis in the context of tumorigenesis. We then review the literature on potential 'danger signals' that may link tumorigenesis and cancer immunosurveillance and discuss the range of immune-regulatory mechanisms that restrict cancer immunity. Finally, we discuss how a better understanding of the interacting pathways governing cell death, danger, and immunity may lead to the development of effective cancer immunotherapies. We propose that the minimum requirements for the induction of clinically relevant immune responses include, on the one hand, the development of therapeutic drugs that can either bypass or rescue intrinsic tumor suppressor pathways while inducing a pro-immunogenic form of cell death and, on the other hand, the concerted combination of immune-stimulatory agents able to enhance tumor-antigen presentation and overcome critical immune-regulatory checkpoints that restrict cancer immunity. [Abstract]

Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, Devera ME, Liang X, Tör M, Billiar T
The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity.
Immunol Rev. 2007 Dec;220(1):60-81.
The response to pathogens and damage in plants and animals involves a series of carefully orchestrated, highly evolved, molecular mechanisms resulting in pathogen resistance and wound healing. In metazoans, damage- or pathogen-associated molecular pattern molecules (DAMPs, PAMPs) execute precise intracellular tasks and are also able to exert disparate functions when released into the extracellular space. The emergent consequence for both inflammation and wound healing of the abnormal extracellular persistence of these factors may underlie many clinical disorders. DAMPs/PAMPs are recognized by hereditable receptors including the Toll-like receptors, the NOD1-like receptors and retinoic-acid-inducible gene I-like receptors, as well as the receptor for advanced glycation end products. These host molecules 'sense' not only pathogens but also misfolded/glycated proteins or exposed hydrophobic portions of molecules, activating intracellular cascades that lead to an inflammatory response. Equally important are means to not only respond to these molecules but also to eradicate them. We have speculated that their destruction through oxidative mechanisms normally exerted by myeloid cells, such as neutrophils and eosinophils, or their persistence in the setting of pathologic extracellular reducing environments, maintained by exuberant necrotic cell death and/or oxidoreductases, represent important molecular means enabling chronic inflammatory states. [Abstract]

Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S, André F, Tursz T, Kroemer G, Zitvogel L
The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy.
Immunol Rev. 2007 Dec;220(1):47-59.
For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens. [Abstract]

Bianchi ME, Manfredi AA
High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity.
Immunol Rev. 2007 Dec;220(1):35-46.
Tissue damage occurs often in the life of mammals and is usually repaired. Dying cells are swiftly phagocytosed, but before disappearing, they alert surrounding cells to activate homeostatic programs. They release signals that recruit inflammatory cells to the site of injury, promote cell migration and cell division to replace dead cells, and activate the immune system in anticipation of microbial invasion. Many of these events involve high-mobility group box 1 protein (HMGB1), a nuclear protein that is released passively when necrotic cells lose the integrity of their membranes. HMGB1 behaves as a trigger of inflammation, attracting inflammatory cells, and of tissue repair, recruiting stem cells and promoting their proliferation. Moreover, HMGB1 activates dendritic cells (DCs) and promotes their functional maturation and their response to lymph node chemokines. Activated leukocytes actively secrete HMGB1 in the microenvironment. Thus, HMGB1 acts in an autocrine/paracrine fashion and sustains long-term repair and defense programs. DCs secrete HMGB1 several hours after contact with the first maturation stimulus; HMGB1 secretion is critical for their ability to reach the lymph nodes, to sustain the proliferation of antigen-specific T cells, to prevent their activation-dependent apoptosis, and to promote their polarization towards a T-helper 1 phenotype. These immune responses will also be directed against self-antigens that DCs process at the time of injury and can lead to autoimmunity. [Abstract]

Obeid M, Tesniere A, Panaretakis T, Tufi R, Joza N, van Endert P, Ghiringhelli F, Apetoh L, Chaput N, Flament C, Ullrich E, de Botton S, Zitvogel L, Kroemer G
Ecto-calreticulin in immunogenic chemotherapy.
Immunol Rev. 2007 Dec;220(1):22-34.
The conventional treatment of cancer relies upon radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Nonetheless, there are circumstances in which conventional anti-cancer therapy can induce a modality of cellular demise that elicits innate and cognate immune responses, which in turn mediate part of the anti-tumor effect. Although different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway, they differ in their capacity to stimulate immunogenic cell death. We discovered that the pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells. Thus, anthracyclines and gamma-irradiation that induce ecto-CRT cause immunogenic cell death, while other pro-apoptotic agents (such as mitomycin C and etoposide) induce neither ecto-CRT nor immunogenic cell death. Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, while exogenous supply of CRT or enforcement of CRT exposure by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. For optimal anti-tumor vaccination and immunogenic chemotherapy, the same cells have to expose ecto-CRT and to succumb to apoptosis; if these events affect different cells, no anti-tumor immune response is elicited. These results may have far reaching implications for tumor immunology because (i) ecto-CRT exposure by tumor cells allows for the prediction of therapeutic outcome and because (ii) the re-establishment of ecto-CRT may ameliorate the efficacy of chemotherapy. [Abstract]

Temkin V, Karin M
From death receptor to reactive oxygen species and c-Jun N-terminal protein kinase: the receptor-interacting protein 1 odyssey.
Immunol Rev. 2007 Dec;220(1):8-21.
Death receptors (DRs) are more than simple killers: they control cell growth, proliferation, and survival, thereby playing a pivotal role in immune and inflammatory responses. Some of these phenomena might be explained by aberrant reactive oxygen species (ROS) production and metabolism, which can lead to oxidative stress. A key signaling molecule of DR-initiated intracellular pathways, receptor-interacting protein 1 (RIP1), orchestrates a complex control of multiple responses and may link DR-associated signaling complexes to ROS production by mitochondria. Yet, RIP1 is also an important regulator of endogenous anti-oxidants and ROS scavenging enzymes, because it is required for nuclear factor kappaB activation that results in expression of anti-apoptotic and anti-oxidant proteins. Alteration of RIP1 function may result in ROS accumulation and abnormal c-Jun N-terminal protein kinase activation, affecting inflammatory responses, innate immunity, stress responses, and cell survival. These molecular mechanisms may be involved in neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. [Abstract]

Zitvogel L, Kroemer G
Death, danger, and immunity: an infernal trio.
Immunol Rev. 2007 Dec;220(1):5-7. [Abstract]

Yan ZQ, Hansson GK
Innate immunity, macrophage activation, and atherosclerosis.
Immunol Rev. 2007 Oct;219187-203.
Inflammation underpins the development of atherosclerosis. Initiation and progression of vascular inflammation involves a complex cellular network, with macrophages as major contributors. Activated macrophages produce proinflammatory mediators, bridge innate and adaptive immunity, regulate lipid retention, and participate directly in vascular repair and remodeling. Recent efforts to elucidate molecular mechanisms involved in the regulation of vascular inflammation in atherosclerosis have implicated several families of innate immune recognition receptors in inflammatory activation during the course of this disease. This article reviews our current understanding of innate immune recognition receptors, signaling pathways, and putative ligands implicated in activation of macrophages in the disease. In its final section, we propose a model for the role of macrophages in bridging inflammation and atherosclerosis from the perspective of innate immune recognition and activation. [Abstract]

Berrington WR, Hawn TR
Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?
Immunol Rev. 2007 Oct;219167-86.
Despite the discovery of the tuberculosis (TB) bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis (MTb). Understanding the genetic and immunologic factors that influence human susceptibility could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. Although a series of studies over the past 50 years suggests that host genetics influences resistance to TB, a comprehensive understanding of which genes and variants are associated with susceptibility is only partially understood. In this article, we review recent advances in our understanding of human variation of the immune system and its effects on macrophage function and influence on MTb susceptibility. We emphasize recent discoveries in human genetic studies and correlate these findings with efforts to understand how these variants alter the molecular and cellular functions that regulate the macrophage response to MTb. [Abstract]

Roozendaal R, Carroll MC
Complement receptors CD21 and CD35 in humoral immunity.
Immunol Rev. 2007 Oct;219157-66.
The complement system is a family of proteins that is involved in both innate and adaptive immunity. Complement receptors CD21 and CD35, which recognize activated products of C3 and C4, are predominantly expressed on B cells and follicular dendritic cells (FDCs) in the mouse. In this review, we focus on the role of FDC-expressed CD21 and CD35 in humoral immunity. They are the principle receptors for uptake and retention of immune complexes. In their absence, memory B-cell survival is markedly impaired. This is likely because of the lack of antigen but could also reflect a role for complement C3d ligand. How antigen is transported to FDCs remains an open question. In recent unpublished work using multiphoton intravital imaging, we found that small protein antigens presented in the lymph drain rapidly into B-cell follicles and are taken up by FDCs in a complement-dependent manner. [Abstract]

Savina A, Amigorena S
Phagocytosis and antigen presentation in dendritic cells.
Immunol Rev. 2007 Oct;219143-56.
Like macrophages and neutrophils, dendritic cells (DCs) are considered professional phagocytes. Even if the three cell types phagocytose parasites, bacteria, cell debris, or even intact cells very efficiently, the functional outcomes of the phagocytic event are quite different. Macrophages and neutrophils scavenge and destroy phagocytosed particles, a critical step in innate immunity. DCs, in contrast, have developed means to 'preserve' useful information from the ingested particles that serve to initiate adaptive immune responses. Thus, both phagosomal degradation and acidification are much lower in DCs than in macrophages or neutrophils. Reduced degradation results in the conservation of antigenic peptides and in their increased presentation on major histocompatibility complex class I and II molecules. In this article, we review the mechanisms that control this delicate equilibrium between phagosomal degradation/cytotoxicity and antigen presentation in the different families of phagocytes. [Abstract]

Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, Di Pucchio T, Connolly J, Fay JW, Pascual V, Palucka AK, Banchereau J
Dendritic cell subsets in health and disease.
Immunol Rev. 2007 Oct;219118-42.
The dendritic cell (DC) system of antigen-presenting cells controls immunity and tolerance. DCs initiate and regulate immune responses in a manner that depends on signals they receive from microbes and their cellular environment. They allow the immune system to make qualitatively distinct responses against different microbial infections. DCs are composed of subsets that express different microbial receptors and express different surface molecules and cytokines. Our studies lead us to propose that interstitial (dermal) DCs preferentially activate humoral immunity, whereas Langerhans cells preferentially induce cellular immunity. Alterations of the DC system result in diseases such as autoimmunity, allergy, and cancer. Conversely, DCs can be exploited for vaccination, and novel vaccines that directly target DCs in vivo are being designed. [Abstract]

Allen LA, McCaffrey RL
To activate or not to activate: distinct strategies used by Helicobacter pylori and Francisella tularensis to modulate the NADPH oxidase and survive in human neutrophils.
Immunol Rev. 2007 Oct;219103-17.
Neutrophils accumulate rapidly at sites of infection, and the ability of these cells to phagocytose and kill microorganisms is an essential component of the innate immune response. Relatively few microbial pathogens are able to evade neutrophil killing. Herein, we describe the novel strategies used by Helicobacter pylori and Francisella tularensis to disrupt neutrophil function, with a focus on assembly and activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. [Abstract]

Nauseef WM
How human neutrophils kill and degrade microbes: an integrated view.
Immunol Rev. 2007 Oct;21988-102.
Neutrophils constitute the dominant cell in the circulation that mediates the earliest innate immune human responses to infection. The morbidity and mortality from infection rise dramatically in patients with quantitative or qualitative neutrophil defects, providing clinical confirmation of the important role of normal neutrophils for human health. Neutrophil-dependent anti-microbial activity against ingested microbes represents the collaboration of multiple agents, including those prefabricated during granulocyte development in the bone marrow and those generated de novo following neutrophil activation. Furthermore, neutrophils cooperate with extracellular agents as well as other immune cells to optimally kill and degrade invading microbes. This brief review focuses attention on two examples of the integrated nature of neutrophil-mediated anti-microbial action within the phagosome. The importance and complexity of myeloperoxidase-mediated events illustrate a collaboration of anti-microbial responses that are endogenous to the neutrophil, whereas the synergy between the phagocyte NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and plasma-derived group IIA phospholipase A(2) exemplifies the collective effects of the neutrophil with an exogenous factor to achieve degradation of ingested staphylococci. [Abstract]

Underhill DM
Collaboration between the innate immune receptors dectin-1, TLRs, and Nods.
Immunol Rev. 2007 Oct;21975-87.
Microbes are complex and present a wide variety of structures that phagocytes may recognize using innate immune receptors. Recognition triggers anti-microbial killing mechanisms and production of inflammatory cytokines and chemokines that orchestrate host defense. As a general rule, no single receptor is likely to be the sole mediator of activation of protective immune responses. Recent studies highlight the importance of collaboration between Toll-like receptors, the nucleotide oligomerization domain (Nod) proteins, and dectin-1 in regulating inflammatory responses. Studies on the molecular mechanisms of cross-talk and synergy between these receptors provide a framework in which to understand the importance of having multiple receptors recognize individual microbes. [Abstract]

Osorio y Fortéa J, Prina E, de La Llave E, Lecoeur H, Lang T, Milon G
Unveiling pathways used by Leishmania amazonensis amastigotes to subvert macrophage function.
Immunol Rev. 2007 Oct;21966-74.
This article provides a summary and discussion of properties of Leishmania amazonensis-loaded mouse macrophages. It illustrates how high-throughput analysis is expected to contribute to deciphering features displayed by macrophages when they are subverted as host cells for replicating Leishmania amastigotes. Firstly, we discuss features of mouse mononuclear phagocytes in steady-state conditions, including the phagocytosis of apoptotic cells. Secondly, we discuss results from ongoing investigations aimed at characterizing transcriptional signatures displayed by BALB/c mouse bone marrow-derived macrophages housing replicating L. amazonensis amastigotes. After a brief presentation on the feasibility of high-throughput microscopy relying on our robust culture system, we share some perspectives on the perpetuation of L. amazonensis in their hosts. Within this latter context, a novel question is formulated and its relevance is discussed: do the Leishmania amastigotes that persist within the mammalian dermis reach a non-replicating developmental stage? If so, is this developmental stage the only one displaying the features required for further development as promastigotes within the sand fly gut lumen? [Abstract]

Prost LR, Sanowar S, Miller SI
Salmonella sensing of anti-microbial mechanisms to promote survival within macrophages.
Immunol Rev. 2007 Oct;21955-65.
Salmonella enterica is a facultative intracellular pathogen that replicates within macrophages. The interaction of this pathogen with mammalian cells is a complex process involving hundreds of bacterial products that are sensed by and alter mammalian hosts. Numerous bacterial genes and their protein products have been identified that are required for Salmonella to resist killing by host innate immunity and to modify host processes. Many of these genes are regulated by a specific bacterial sensor, the PhoQ protein, which responds to the acidified phagosome environment. PhoQ is a sensor histidine kinase, which when activated in vivo within acidified macrophage phagosomes, regulates cell surface modifications that promote resistance to antimicrobial peptides and oxidative stress, alter the phagosome to promote intracellular survival, and reduce innate immune recognition. In this review, we discuss mechanisms by which Salmonella interacts with macrophages and focus in detail on recent reports describing the role of antimicrobial peptides and pH in PhoQ activation. [Abstract]

Rohde K, Yates RM, Purdy GE, Russell DG
Mycobacterium tuberculosis and the environment within the phagosome.
Immunol Rev. 2007 Oct;21937-54.
Once across the barrier of the epithelium, macrophages constitute the primary defense against microbial invasion. For most microbes, the acidic, hydrolytically competent environment of the phagolysosome is sufficient to kill them. Despite our understanding of the trafficking events that regulate phagosome maturation, our appreciation of the lumenal environment within the phagosome is only now becoming elucidated through real-time functional assays. The assays quantify pH change, phagosome/lysosome fusion, proteolysis, lipolysis, and beta-galactosidase activity. This information is particularly important for understanding pathogens that successfully parasitize the endosomal/lysosomal continuum. Mycobacterium tuberculosis infects macrophages through arresting the normal maturation process of the phagosome, retaining its vacuole at pH 6.4 with many of the characteristics of an early endosome. Current studies are focusing on the transcriptional response of the bacterium to the changing environment in the macrophage phagosome. Manipulation of these environmental cues, such as preventing the pH drop to pH 6.4 with concanamycin A, abrogates the majority of the transcriptional response in the bacterium, showing that pH is the dominant signal that the bacterium senses and responds to. These approaches represent our ongoing attempts to unravel the discourse that takes place between the pathogen and its host cell. [Abstract]

Yeung T, Grinstein S
Lipid signaling and the modulation of surface charge during phagocytosis.
Immunol Rev. 2007 Oct;21917-36.
Phagocytosis is an important component of innate and adaptive immunity. The formation of phagosomes and the subsequent maturation that capacitates them for pathogen elimination and antigen presentation are complex processes that involve signal transduction, cytoskeletal reorganization, and membrane remodeling. Lipids are increasingly appreciated to play a crucial role in these events. Sphingolipids, cholesterol, and glycerophospholipids, notably the phosphoinositides, are required for the segregation of signaling microdomains and for the generation of second messengers. They are also instrumental in the remodeling of the actin cytoskeleton and in directing membrane traffic. They accomplish these feats by congregating into liquid-ordered domains, by generating active metabolites that activate receptors, and by recruiting and anchoring specific protein ligands to the membrane, often altering their conformation and catalytic activity. A less appreciated role of acidic phospholipids is their contribution to the negative surface charge of the inner leaflet of the plasmalemma. The unique negativity of the inner aspect of the plasma membrane serves to attract and anchor key signaling and effector molecules that are required to initiate phagosome formation. Conversely, the loss of charge that accompanies phospholipid metabolism as phagosomes seal facilitates the dissociation of proteins and the termination of signaling and cytoskeleton assembly. In this manner, lipids provide a binary electrostatic switch to control phagocytosis. [Abstract]

Recent Articles in AIDS

Parikh A, Desilva MB, Cakwe M, Quinlan T, Simon JL, Skalicky A, Zhuwau T
Exploring the Cinderella myth: intrahousehold differences in child wellbeing between orphans and non-orphans in Amajuba District, South Africa.
AIDS. 2007 Nov;21 Suppl 7S95-S103.
OBJECTIVE:: To determine whether differences in wellbeing (defined by a variety of education and health outcomes) exist between recent school-aged orphans and non-orphans who live in the same household in a context of high HIV/AIDS mortality in KwaZulu Natal, South Africa. DESIGN:: The data come from the first 2 years (2004-2006) of an ongoing 3-year longitudinal cohort study in a district in KwaZulu-Natal, the Amajuba Child Health and Well-being Research Project. Using stratified cluster sampling based on school and age, we constructed a cohort of 197 recent orphans and 528 non-orphans aged 9-16 years and their households and caregivers. Household heads, caregivers, and children were interviewed regarding five domains of child wellbeing: demographic, economic, educational, health/nutrition/lifestyle, and psychosocial status. METHODS:: The analytical sample consists of 174 children (87 orphans and 87 comparable non-orphans who live together) at baseline and 124 children in round 2. We estimated a linear regression model using household fixed effects for continuous outcomes (grade adjusted for age, annual expenditure on schooling and body mass index) and a logit model using household fixed effects for categorical variables (malnutrition) to compare co-resident orphans and non-orphans. RESULTS:: We found no statistically significant differences in most education, health and labour outcomes between orphans and the non-orphans with whom they live. Paternal orphans are more likely to be behind in school, and recent mobility has a positive effect on schooling outcomes. [Abstract]

Timaeus IM, Boler T
Father figures: the progress at school of orphans in South Africa.
AIDS. 2007 Nov;21 Suppl 7S83-93.
OBJECTIVE:: To examine the progress in their schooling of maternal and paternal orphans in a province of South Africa with high AIDS mortality and contrast it with that of both children who lived in different households from their parents and children who resided with their parents. METHODS:: The KwaZulu-Natal Income Dynamics Study is a panel of households first interviewed in 1993. The 1998 and 2004 waves of fieldwork collected 5477 reports on children aged 8-20 years. We studied the determinants of the proportion of these children who had completed 2+ grades fewer than expected for their year of birth using both household fixed-effects models and difference-in-difference models fitted to children reported on twice. RESULTS:: Co-residence with a well-educated mother benefited children's schooling, but the fixed-effects models provide no evidence that maternal orphanhood or living apart from their mother adversely affected children's schooling. In contrast, both paternal orphanhood and belonging to a different household from one's father resulted in slower progress at school. Although absence of the father was associated with household poverty, this was not why it was associated with falling behind at school. DISCUSSION:: Both the substantial benefits of living with their fathers for children's schooling and the limited importance of maternal orphanhood conflict with the results of most studies in this issue, including those of other research in the same part of South Africa. These findings caution against drawing general conclusions about the impact of the AIDS epidemic from a few studies of geographically localized populations. [Abstract]

Collins DL, Leibbrandt M
The financial impact of HIV/AIDS on poor households in South Africa.
AIDS. 2007 Nov;21 Suppl 7S75-81.
BACKGROUND:: Rising mortality rates caused by HIV/AIDS in South Africa have substantial and lingering impacts on poor households. METHODS:: This is a descriptive paper using a new dataset of daily income, expenditure and financial transactions collected over a year from a total of 181 poor households in South African rural and urban areas. One of the key pathways through which HIV/AIDS impacts on household wellbeing is through the socioeconomic impacts of death, which this dataset is especially useful in quantifying. RESULTS:: The key impacts of death on households are funerals and the loss of income. Funerals often cost up to 7 months of income. Nearly all households in the sample attempt to cover such costs by holding a portfolio of funeral insurance. Despite these efforts to insure against funeral costs, 61% of households are underinsured against the cost of a funeral. Nearly half the sample households are dependent on a regular wage earner, and another quarter are dependent on a grant recipient. Eighty per cent of these households would lose over half of their monthly income should the highest income recipient in the household die. Even by selling liquid assets, only one third of the sample households would be able to maintain their pre-death living standards for a year or more. CONCLUSION:: Death poses substantial and lingering burdens from the funerals that surviving household members need to finance and the ongoing loss of income once brought into the household by the deceased. These costs pose so great a threat to households that they dominate household saving and insurance behavior. [Abstract]

Gillespie S, Kadiyala S, Greener R
Is poverty or wealth driving HIV transmission?
AIDS. 2007 Nov;21 Suppl 7S5-S16.
Evidence of associations between socioeconomic status and the spread of HIV in different settings and at various stages of the epidemic is still rudimentary. Few existing studies are able to track incidence and to control effectively for potentially confounding factors. This paper reviews the findings of recent studies, including several included in this volume, in an attempt to uncover the degree to which, and the pathways through which, wealth or poverty is driving transmission in sub-Saharan Africa. We investigate the question of whether the epidemic is transitioning from an early phase in which wealth was a primary driver, to one in which poverty is increasingly implicated. The paper concludes by demonstrating the complexity and context-specificity of associations and the critical influence of certain contextual factors such as location, gender and age asymmetries, the mobility of individuals, and the social ecology of HIV transmission. Whereas it is true that poor individuals and households are likely to be hit harder by the downstream impacts of AIDS, their chances of being exposed to HIV in the first place are not necessarily greater than wealthier individuals or households. What is clear is that approaches to HIV prevention need to cut across all socioeconomic strata of society and they need to be tailored to the specific drivers of transmission within different groups, with particular attention to the vulnerabilities faced by youth and women, and to the dynamic and contextual nature of the relationship between socioeconomic status and HIV. [Abstract]

Dinkelman T, Lam D, Leibbrandt M
Household and community income, economic shocks and risky sexual behavior of young adults: evidence from the Cape Area Panel Study 2002 and 2005.
AIDS. 2007 Nov;21 Suppl 7S49-56.
OBJECTIVE:: To describe recent trends in adolescent sexual behavior in Cape Town, South Africa, and to determine whether household and community poverty and negative economic shocks predict risky sexual behavior. DATA:: Matched survey data on 2993 African and coloured youth from the Cape Area Panel Study 2002 and 2005. MAIN OUTCOME MEASURES:: Sexual debut, multiple sexual partners in past year, condom use at last sex, measured in 2002 and 2005. METHODS:: We tested for changes over time in reported sexual behavior and estimate multivariate probit models to measure the association between 2002 individual, household and community characteristics and 2005 sexual behavior. RESULTS:: There was a statistically significant increase in condom use and a decrease in the incidence of multiple sexual partners between 2002 and 2005 for young women aged 17-22 years. Young women in households with 10% higher income were 0.53% less likely to debut sexually by 2005; young men in communities with a 10% higher poverty rate were 5% less likely to report condom use at last sex. Negative economic shocks are associated with a 0.04% increase in the probability of multiple partnerships for young women. Education is positively correlated with sexual debut for young women and with multiple partnerships for both sexes. CONCLUSION:: Trends in sexual behavior between 2002 and 2005 indicate significant shifts towards safer practices. There is little evidence of a relationship between negative economic shocks, household and community poverty, and risky behavior. We hypothesize that the unexpected positive relationship between education and sexual debut may be driven by peer effects in schools with substantial age mixing. [Abstract]

Hargreaves JR, Bonell CP, Morison LA, Kim JC, Phetla G, Porter JD, Watts C, Pronyk PM
Explaining continued high HIV prevalence in South Africa: socioeconomic factors, HIV incidence and sexual behaviour change among a rural cohort, 2001-2004.
AIDS. 2007 Nov;21 Suppl 7S39-48.
OBJECTIVES:: To estimate HIV incidence and explore evidence for changing sexual behaviour over time among men and women belonging to different socioeconomic groups in rural South Africa. DESIGN AND METHODS:: A cohort study conducted between 2001 and 2004; 3881 individuals aged 14-35 years enumerated in eight villages were eligible. At least three household visits were made to contact each eligible respondent at both timepoints. Sexual behaviour data were collected in structured, respondent-focused interviews. HIV serostatus was assessed using an oral fluid enzyme-linked immunosorbent assay at each timepoint. RESULTS:: Data on sexual behaviour were available from 1967 individuals at both timepoints. A total of 1286 HIV-negative individuals at baseline contributed to the analysis of incidence. HIV incidence was 2.2/100 person-years among men and 4.9/100 person-years in women, among whom it was highest in the least educated group. Median age at first sex was lower among later birth cohorts. A higher number of previously sexually active individuals reported having multiple partners in the past year in 2004 than 2001. Condom use with non-spousal partners increased from 2001 to 2004. Migrant men more often reported multiple partners. Migrant and more educated individuals of both sexes and women from wealthier households reported higher levels of condom use. DISCUSSION:: HIV incidence is high in rural South Africa, particularly among women of low education. Some risky sexual behaviours (early sexual debut, having multiple sexual partners) are becoming more common over time. Condom use is increasing. Existing HIV prevention strategies have only been partly effective in generating population-level behavioural change. [Abstract]

Mishra V, Assche SB, Greener R, Vaessen M, Hong R, Ghys PD, Boerma JT, Van Assche A, Khan S, Rutstein S
HIV infection does not disproportionately affect the poorer in sub-Saharan Africa.
AIDS. 2007 Nov;21 Suppl 7S17-28.
BACKGROUND:: Wealthier populations do better than poorer ones on most measures of health status, including nutrition, morbidity and mortality, and healthcare utilization. OBJECTIVES:: This study examines the association between household wealth status and HIV serostatus to identify what characteristics and behaviours are associated with HIV infection, and the role of confounding factors such as place of residence and other risk factors. METHODS:: Data are from eight national surveys in sub-Saharan Africa (Kenya, Ghana, Burkina Faso, Cameroon, Tanzania, Lesotho, Malawi, and Uganda) conducted during 2003-2005. Dried blood spot samples were collected and tested for HIV, following internationally accepted ethical standards and laboratory procedures. The association between household wealth (measured by an index based on household ownership of durable assets and other amenities) and HIV serostatus is examined using both descriptive and multivariate statistical methods. RESULTS:: In all eight countries, adults in the wealthiest quintiles have a higher prevalence of HIV than those in the poorer quintiles. Prevalence increases monotonically with wealth in most cases. Similarly for cohabiting couples, the likelihood that one or both partners is HIV infected increases with wealth. The positive association between wealth and HIV prevalence is only partly explained by an association of wealth with other underlying factors, such as place of residence and education, and by differences in sexual behaviour, such as multiple sex partners, condom use, and male circumcision. CONCLUSION:: In sub-Saharan Africa, HIV prevalence does not exhibit the same pattern of association with poverty as most other diseases. HIV programmes should also focus on the wealthier segments of the population. [Abstract]

Smith J, Mushati P, Kurwa F, Mason P, Gregson S, Lopman B
Changing patterns of adult mortality as the HIV epidemic matures in Manicaland, eastern Zimbabwe.
AIDS. 2007 Nov;21 Suppl 6S81-6.
BACKGROUND:: HIV prevalence declined in Manicaland, eastern Zimbabwe, between 1998 and 2003. During this period, adult mortality in men was stable, whereas female mortality increased to levels similar to those of men. We examine the trends in mortality from 2003 to 2005. METHODS:: A population-based cohort was recruited from a household census in 12 communities. A baseline survey was conducted between 1998 and 2000, with the first and second follow-up surveys occurring after 3 and 5 years, respectively. Using checklists of the resident population at the previous round, adult deaths were reported to enumerators by surviving household members or community informants. RESULTS:: Age-standardized adult mortality rates for men increased slightly but not significantly over time (1998-2000: 24/1000 person-years; 2001-2002: 26/1000 person-years; 2003-2005: 31/1000 person-years), reflecting a sharp rise in mortality among HIV-positive individuals (62, 79 and 105 per 1000 person-years). Female mortality rose sharply initially but levelled off after 2001 (15, 26 and 26 per 1000 person-years) also caused by the pronounced increase in mortality among HIV-positive women (35, 75 and 88/1000 person-years; 7/1000 person-years for HIV-negative men and women in all periods); 69% of adult male deaths and 74% of adult female deaths were attributable to HIV/AIDS in 2003-2005. In men, mortality was similar and stable in towns, estates, roadside business centres and subsistence farming areas. In women, mortality rose in towns and subsistence farming areas between 1998 and 2002 and was greater in towns than in other locations. CONCLUSION:: Recent data indicate that adult mortality may be stabilizing in eastern Zimbabwe after the recent downturn in HIV prevalence. [Abstract]

Isingo R, Zaba B, Marston M, Ndege M, Mngara J, Mwita W, Wringe A, Beckles D, Changalucha J, Urassa M
Survival after HIV infection in the pre-antiretroviral therapy era in a rural Tanzanian cohort.
AIDS. 2007 Nov;21 Suppl 6S5-S13.
BACKGROUND:: Survival patterns after HIV infection in African populations in the era before antiretroviral therapy (ART) form an important baseline for measuring future successes of treatment programmes. Few studies have followed seroconverters for 10 or more years to describe such patterns. METHODS:: The Kisesa open cohort study conducted four rounds of village-based HIV testing and 20 rounds of household-based demographic surveillance between 1994 and 2006. Approximate infection dates were established for individual seroconverters by allocating a date between the last negative and first positive test. Person-years lived post-infection were computed, allowing for left truncation and right censoring, and Kaplan-Meier survival functions were constructed, truncating the analysis at the start of 2005 when ART first became available in the community. Weibull models were fitted to estimate median survival time, and parametric regression methods were used to investigate the influence of sex and age at infection. RESULTS:: A total of 369 seroconverters were identified, providing 890 person-years of follow-up during which 44 deaths were observed. The Kaplan-Meier function showed 67% surviving 9 years post-infection, and the overall predicted median survival was 11.5 years. Survival was strongly related to age at infection (hazard ratio 1.06 for each additional year of age, and weakly to sex. A strong effect of age was evident even after allowing for mortality from non-HIV-related causes using cause deletion methods to estimate net mortality. CONCLUSION:: The survival of HIV-infected individuals was comparable to that reported in developed country studies before the introduction of HAART. Survival patterns in Kisesa are marginally more favourable than those reported in cohort studies in Uganda. [Abstract]

Van der Paal L, Shafer LA, Todd J, Mayanja BN, Whitworth JA, Grosskurth H
HIV-1 disease progression and mortality before the introduction of highly active antiretroviral therapy in rural Uganda.
AIDS. 2007 Nov;21 Suppl 6S21-9.
OBJECTIVE:: To provide estimates of survival and progression to different HIV disease endpoints after HIV infection among adults in a rural Ugandan setting. DESIGN:: A prospective population-based cohort study. METHODS:: Eligible individuals at least 15 years of age with documented HIV seroconversion were recruited from a general population cohort in rural Uganda, along with a randomly selected proportion of HIV-prevalent and HIV-negative individuals. All participants were followed up every 3 months, and CD4 cell counts taken every 6 months in HIV-positive participants. Life tables and Kaplan-Meier functions were used to estimate survival patterns for all endpoints [death, time to World Health Organization (WHO) stage 2, 3, AIDS and CD4 cell count < 200 cells/mul]. Analysis of follow-up time was truncated when antiretroviral therapy (ART) became available in the area in January 2004. RESULTS:: We recruited 240 HIV incident cases, 108 prevalent cases and 257 HIV-negative controls. Crude mortality rates were 70.0 per 1000 person-years in HIV-positive, and 12.1 per 1000 person-years in HIV-negative individuals. The median time from seroconversion to death was 9.0 years (N = 240) and 6.2 years to a CD4 cell count less than 200 cells/mul or WHO stage 4 (N = 229). The median time from ART eligibility (CD4 cell count < 200 cells/mul, < 350 cells/mul and WHO stage 3, or WHO stage 4) to death was 34.7 months. Older age at seroconversion was a risk factor for faster progression to death and ART eligibility. CONCLUSION:: HIV progression in this African cohort is similar to that reported in industrialized countries before the widespread introduction of ART. [Abstract]

McGrath N, Kranzer K, Saul J, Crampin AC, Malema S, Kachiwanda L, Zaba B, Jahn A, Fine PE, Glynn JR
Estimating the need for antiretroviral treatment and an assessment of a simplified HIV/AIDS case definition in rural Malawi.
AIDS. 2007 Nov;21 Suppl 6S105-13.
BACKGROUND:: Surveillance in the era of antiretroviral therapy (ART) requires estimates of HIV prevalence as well as the proportion eligible for ART. We estimated HIV prevalence and assessed field staging of individuals to estimate the burden of HIV disease needing treatment in rural Malawi. METHODS:: Adults aged 18-59 years in a demographic surveillance system were interviewed, examined, and HIV counselled and tested. Staging that used a simplified version of the WHO criteria ('field checklist') was compared with staging by a medical assistant using a 'clinic checklist' and to CD4 cell results. RESULTS:: A total of 2129 of 2303 eligible adults (92.4%) were traced, and 2047 (96.1%) participated. Of the 1443 participants (70.5%) tested, 11.6% were HIV positive. ART eligibility classification by the field and clinic checklists were concordant in 122 of 133 HIV-positive individuals. Compared with the clinic checklist, the field checklist had a sensitivity of 50% and a specificity of 96%. Including those already known to be on ART, staging by the field and clinic checklists estimated ART eligibility at 16.3 and 17.7% of HIV-positive individuals, respectively. Using CD4 cell count under 250 cells/mul or WHO stage III/IV, the Malawi national programme criteria, 38% of HIV-positive individuals were eligible for ART, compared with 31% based on the 2006 WHO criteria of CD4 cell count under 200 cells/mul or WHO stage IV or CD4 cell count of 200-350 cells/mul and WHO stage III. CONCLUSION:: The field checklist was not a suitable tool for individual staging. Criteria for ART eligibility based on clinical staging alone missed two-thirds of those eligible by clinical staging and CD4 cell count. [Abstract]

Pedrol E, Deig E
Reply to Crane et al., 'Amprenavir and didanosine are associated with declining kidney function among patients receiving tenofovir'.
AIDS. 2007 Nov 30;21(18):2566. [Abstract]

Lopriore E, Rozendaal L, Gelinck LB, Bökenkamp R, Boelen CC, Walther FJ
Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART.
AIDS. 2007 Nov 30;21(18):2564-5. [Abstract]

Pagano G, Dodi F, Camera M, Passalacqua G, Malfatto E, De Maria A
Tubercular tracheoesophageal fistulas in AIDS patients: primary repair and no surgery required?
AIDS. 2007 Nov 30;21(18):2561-4. [Abstract]

Helleringer S, Kohler HP, Chimbiri A
Characteristics of external/bridge relationships by partner type and location where sexual relationship took place.
AIDS. 2007 Nov 30;21(18):2560-1. [Abstract]

Mounzer K, DiNardo A, Goldstein K
Thrombotic thrombocytopenic purpura during immune reconstitution.
AIDS. 2007 Nov 30;21(18):2559-60. [Abstract]

Whitworth JA, Biraro S, Shafer LA, Morison LA, Quigley M, White RG, Mayanja BN, Ruberantwari A, Van der Paal L
Confusing association with causation?, a response to Brewer et al., 'Valid evaluation of iatrogenic and sexual HIV transmission requires proof'.
AIDS. 2007 Nov 30;21(18):2558-9. [Abstract]

Brewer DD, Potterat JJ, Gisselquist D, Dinsmore WW, St Lawrence JS, Brody S
Valid evaluation of iatrogenic and sexual HIV transmission requires proof.
AIDS. 2007 Nov 30;21(18):2556-7; author reply 2558-9. [Abstract]

Thorne C, Townsend CL, Peckham CS, Newell ML, Tookey PA
Pregnancies in young women with vertically acquired HIV infection in Europe.
AIDS. 2007 Nov 30;21(18):2552-6. [Abstract]

Tamalet C, Tomei C, Henry M, Solas C, Villacian J, Colson P
Selection of L74V mutation in reverse transcriptase of HIV-1 subtype D by a tenofovir DF-lamivudine based regimen.
AIDS. 2007 Nov 30;21(18):2551-2. [Abstract]

Lacombe K, Boyd A, Desvarieux M, Serfaty L, Bonnord P, Gozlan J, Molina JM, Miailhes P, Lascoux-Combe C, Gault E, Girard PM
Impact of chronic hepatitis C and/or D on liver fibrosis severity in patients co-infected with HIV and hepatitis B virus.
AIDS. 2007 Nov 30;21(18):2546-9.
The histological study on the reciprocal influence of chronic hepatitis C (HCV) and/or delta (HDV) on liver damage in a cohort of 134 HIV-HBV co-infected patients concluded on a significant association between HDV co-infection (noted in 13 patients) and Metavir F3-F4 liver fibrosis score [odds ratio (OR) = 7.08, 95% confidence interval (CI) = 1.06-47.28 for HBV-HDV, OR = 10.02, 95% CI = 1.03-97.42 for HBV-HCV-HDV, compared to OR = 1.76, 95% CI = 0.50-6.17 for HBV alone]. Co-treatment of other multiple viral hepatitis infections should also be taken into consideration, especially in the case of chronic HDV. [Abstract]

Hadigan C, Mazza S, Crum D, Grinspoon S
Rosiglitazone increases small dense low-density lipoprotein concentration and decreases high-density lipoprotein particle size in HIV-infected patients.
AIDS. 2007 Nov 30;21(18):2543-6.
After 12 weeks of rosiglitazone treatment, significant increases in total and small dense low-density lipoprotein, and the total: high-density lipoprotein (HDL)-cholesterol ratio were found. The large HDL concentration and HDL particle size decreased significantly with rosiglitazone compared with placebo. These data indicate the production of a more atherogenic lipid profile with rosiglitazone, a consideration when selecting treatment for the growing population of HIV-infected patients with type 2 diabetes and dyslipidemia. [Abstract]

Shastry L, Wilson T, Lascher S, Nord JA
The utility of aspartate aminotransferase/platelet ratio index in HIV/hepatitis C-co-infected patients.
AIDS. 2007 Nov 30;21(18):2541-3.
Liver biopsy is currently the gold standard for determining the stage of liver fibrosis. There are risks associated with liver biopsy; therefore, surrogate markers to predict the severity of disease would be useful. We studied 50 patients with HIV/hepatitis C co-infection who had liver biopsies and determined that no patient with an aspartate aminotransferase/platelet ratio index (APRI) of 0.6 or less had stage F3 or F4 disease. The APRI is useful for excluding advanced disease in this patient population. [Abstract]

Khalsa A, Karim R, Mack WJ, Minkoff H, Cohen M, Young M, Anastos K, Tien PC, Seaberg E, Levine AM
Correlates of prevalent hypertension in a large cohort of HIV-infected women: Women's Interagency HIV Study.
AIDS. 2007 Nov 30;21(18):2539-41.
Correlates of hypertension were assessed in 1266 HIV-positive and 368 HIV-negative women in the Women's Interagency HIV Study. Hypertension prevalence was similar in HIV-positive and HIV-negative women (26 versus 28%, P = 0.38). Factors associated with hypertension included increasing age (P < 0.0001), African-American race (P < 0.0001), and body mass index greater than 30 kg/m (P < 0.0001), whereas current pregnancy was protective (P < 0.04). HIV infection, CD4 cell count, HIV-1 viral load, and antiretroviral therapy were not associated with hypertension. [Abstract]

Melby TE, Despirito M, Demasi RA, Heilek G, Thommes JA, Greenberg ML, Graham N
Association between specific enfuvirtide resistance mutations and CD4 cell response during enfuvirtide-based therapy.
AIDS. 2007 Nov 30;21(18):2537-9.
Analysis of CD4 cell responses during 48 weeks of enfuvirtide therapy after virological failure (analysis of covariance) demonstrated significant associations between V38 mutations (n = 58 subjects) and continued CD4 cell increases and between Q40 mutations (n = 8) and loss of CD4 cell benefit (+34 versus -95 cells/mul, P < 0.001). Subjects with N43 (n = 20) or other mutations (n = 48) had intermediate CD4 cell responses. These data suggest that key enfuvirtide resistance mutations may be associated with reduced viral pathogenicity in vivo. [Abstract]

Nacher M, Vantilcke V, Huber F, Mahamat A, El Guedj M, Randrianjohany A, Clyti E, Aznar C, Carme B, Couppié P
Increased incidence of mucosal candidiasis after HAART initiation: a benign form of immune reconstitution disease?
AIDS. 2007 Nov 30;21(18):2534-6.
Immune reconstitution after HAART initiation is often complicated by adverse clinical manifestations caused either by the unmasking of preexisting untreated opportunistic infections or the clinical deterioration of a known and treated opportunistic infection. The present study was conducted to determine whether the initiation of HAART was followed by an increase in the incidence of mucosal candidiases, a possible manifestation of immune reconstitution disease of the unmasking type. [Abstract]

Waters LJ, Mandalia S, Gazzard B, Nelson M
Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience.
AIDS. 2007 Nov 30;21(18):2533-4.
Suspected hypersensitivity is the main reason for the early discontinuation of abacavir. After the observation that the risk of hypersensitivity correlated with ethnicity, the presence of the HLA allele B5701 was found to be the strongest retrospective predictor of hypersensitivity. Two prospective cohorts have since demonstrated a significant reduction in abacavir hypersensitivity rates with the use of prospective human leukocyte antigen screening. We describe our experience of prospective HLA-B5701 testing and the impact on rates of abacavir hypersensitivity. [Abstract]

Ginsburg AS, Hoblitzelle CW, Sripipatana TL, Wilfert CM
Provision of care following prevention of mother-to-child HIV transmission services in resource-limited settings.
AIDS. 2007 Nov 30;21(18):2529-32.
OBJECTIVE: To evaluate the provision of care for mother and child after institution of prevention of mother-to-child transmission (PMTCT) of HIV services. DESIGN: As part of an effort to improve services, we undertook a review of our multicountry PMTCT program. METHODS: Review of key indicators from our PMTCT database and reporting practices from January 2005 to June 2006 throughout 18 resource-limited countries. RESULTS: 1 066 606 pregnant women were counseled and tested, and 102 336 tested HIV-positive. Antiretroviral prophylaxis was dispensed to 81 384 mothers and 52 342 HIV-exposed infants. From available reporting, 1388 pregnant women were dispensed antiretroviral drugs for treatment and 9060 children received cotrimoxazole prophylaxis at 6 weeks. CONCLUSIONS: PMTCT services are integrated into maternal-child health services but adult and pediatric care and treatment programs often function independently, without coordination or linkages. Integrating care into maternal-child health services and linking mother's HIV status to child are necessary for HIV-infected mothers and HIV-exposed children to receive appropriate follow-up and treatment. [Abstract]

Muga R, Ferreros I, Langohr K, de Olalla PG, Del Romero J, Quintana M, Alastrue I, Belda J, Tor J, Pérez-Hoyos S, Del Amo J
Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART.
AIDS. 2007 Nov 30;21(18):2521-7.
OBJECTIVE: To analyse incidence and determinants of tuberculosis in HIV-seroconverters before and after the introduction of HAART. METHODS: Data from a multicenter cohort study of 2238 HIV-seroconverters between the 1980s and 2004 were analysed and censored by December 2004. Calendar year at risk intervals were pre-1992, 1992-1996 and 1997-2004. Incident tuberculosis was calculated as cases per 1000 person-years (p-y). Survival analyses using Kaplan-Meier and multivariate Cox regression allowing for late-entry were used. Proportional hazards assumptions were checked with tests based on Schoenfeld residuals. RESULTS: Overall, 173 (7.7%) patients developed tuberculosis over 23 698 p-y at a rate of 7.3 cases per 1000 p-y [95% confidence interval (CI), 6.3-8.5]. Incident tuberculosis was higher in intravenous drug-users (IDUs), 12.3 per 1000 p-y compared with persons infected sexually, 3.8 per 1000 p-y (P < 0.001), and persons with clotting disorders (PCD), 2.7 per 1000 p-y (P < 0.001). A decreasing tuberculosis incidence trend was observed from 1995 in all categories. Highest tuberculosis rates, 44 per 1000 p-y, were observed prior to 1997 in IDUs infected with HIV for 11 years. In multivariable analyses women were less likely to develop tuberculosis [relative hazard (RH), 0.62; 95% CI, 0.41-0.96; P < 0.05) and IDUs were more likely to develop tuberculosis (RH, 3.0; 95% CI, 1.72-5.26, P < 0.001). In the HAART era, the hazard of developing tuberculosis was 70% lower (RH, 0.31; 95% CI, 0.17-0.54; P < 0.001). Before 1997, the risk of tuberculosis increased with time since HIV seroconversion, whereas it remained nearly constant in the HAART era. CONCLUSIONS: Since the mid-1990s important decreases in tuberculosis have been observed in HIV-seroconverters that probably reflect the impact of both HAART and tuberculosis control programmes. [Abstract]

Sanders EJ, Graham SM, Okuku HS, van der Elst EM, Muhaari A, Davies A, Peshu N, Price M, McClelland RS, Smith AD
HIV-1 infection in high risk men who have sex with men in Mombasa, Kenya.
AIDS. 2007 Nov 30;21(18):2513-20.
BACKGROUND: The role of homosexuality and anal sex practices in the African HIV -1 epidemic is not well described. We aimed to assess the risk factors for prevalent HIV-1 infection among men who have sex with men (MSM) to guide HIV-1 prevention efforts. METHODS: Socio-behavioural characteristics, signs and symptoms of sexually transmitted diseases (STD), and serological evidence of HIV-1 were determined for 285 MSM at enrolment into a vaccine preparedness cohort study. We used multivariate logistic regression to assess risk factors for prevalent HIV-1 infection. RESULTS: HIV-1 prevalence was 43.0% [49/114, 95% confidence interval (CI), 34-52%] for men who reported sex with men exclusively (MSME), and 12.3% (21/171, 95% CI, 7-17%) for men who reported sex with both men and women (MSMW). Eighty-six (75%) MSME and 69 (40%) MSMW reported recent receptive anal sex. Among 174 MSM sexually active in the last week, 44% reported no use of condoms with casual partners. In the previous 3 months, 210 MSM (74%) reported payment for sex, and most clients (93%) were local residents. Prevalent HIV-1 infection was associated with recent receptive anal sex [odds ratio (OR), 6.1; 95% CI, 2.4-16], exclusive sex with men (OR, 6.3; 95% CI, 2.3-17), and increasing age (OR, 1.1 per year; 95% CI, 1.04-1.12). Only four MSM reported injecting drug use. CONCLUSIONS: The high prevalence of HIV-1 in Kenyan MSM is probably attributable to unprotected receptive anal sex. There is an urgent need for HIV-1 prevention programmes to deliver targeted risk-reduction interventions and STD services to MSM in Kenya. [Abstract]