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Vaccines given a boost A feature of many successful vaccines is the induction of memory B cells and long-lived plasma cells that can secrete neutralizing antibodies for a lifetime. The mechanisms that stimulate such persistent responses remain poorly understood. Bali Pulendran and colleagues show that nanoparticles containing two Toll-like receptor ligands, proteins with important roles in innate immunity, can boost the magnitude and persistence of vaccine-elicited antibody responses in primates, improving vaccine-mediated protection against influenza virus. Here it is shown that nanoparticles containing two Toll-like receptor ligands can boost the magnitude and persistence of vaccine-elicited antibody responses in primates, improving vaccine-mediated protection against influenza virus. Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs) 1 , 2 . For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed 3 , activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines 4 , 5 . Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines 6 , which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.

Keeping T H 17 cells under wraps Interleukin-17-producing T helper (T H 17) cells serve an important role in the immune system, but are strongly implicated in the pathogenesis of numerous autoimmune diseases including rheumatoid arthritis and multiple sclerosis. How the immune system controls T H 17 cells in vivo remains unclear. Using mice in which tolerance was induced by CD3-specific antibody, a model of sepsis and influenza A viral infection, Esplugues et al . demonstrate that T H 17 cells are kept in check by redirecting the cells to the small intestine where they are eliminated or re-programmed to acquire immunosuppressive and regulatory properties. This work identifies the gastrointestinal tract as a site for control of T H 17 cells. Interleukin (IL)-17-producing T helper cells (T H 17) are a recently identified CD4 + T cell subset distinct from T helper type 1 (T H 1) and T helper type 2 (T H 2) cells 1 . T H 17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE) 2 , the mouse model for multiple sclerosis. The factors that are needed for the generation of T H 17 cells have been well characterized 3 , 4 , 5 , 6 . However, where and how the immune system controls T H 17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory T H 17 cells can be redirected to and controlled in the small intestine. T H 17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that T H 17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory T H 17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rT H 17). These results identify mechanisms limiting T H 17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of T H 17 cells.

Learning to tolerate friendly bacteria Understanding how the immune system becomes tolerant to foreign antigens from commensal bacteria is a fundamental question, as breakdown of tolerance can result in unwanted responses such as inflammatory bowel disease. It has been suggested that tolerogenic regulatory T (T reg ) cells are generated in response to commensal bacteria, but there is little direct evidence to support this hypothesis. A study of the colonic T-cell antigen receptor repertoire of mice now shows that microbial antigens direct the generation of antigen-specific inducible T reg cells in the colon. Commensal-induced T reg cells seem to maintain mucosal tolerance and protect mice from colitis. The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3 + regulatory T (T reg ) cells 1 . However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease 2 , 3 , 4 . Here we show that encounter with commensal microbiota results in the peripheral generation of T reg cells rather than pathogenic effectors. We observed that colonic T reg cells used T-cell antigen receptors (TCRs) different from those used by T reg cells in other locations, implying an important role for local antigens in shaping the colonic T reg -cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon T reg TCRs. These TCRs did not facilitate thymic T reg -cell development, implying that many colonic T reg cells arise instead by means of antigen-driven peripheral T reg -cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimaeras and a TCR transgenic line revealed that microbiota indigenous to our mouse colony was required for the generation of colonic T reg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo T reg -cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of T reg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.

Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection. The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance. Immune surveillance role for MAIT cells Although mucosal-associated invariant T (MAIT) cells comprise up to 10% of the human T-cell population, surprisingly little is known about their role in physiology and pathology. This is in large part because the identity of the antigen or antigens recognized by MAIT cells in an MR1-restricted manner is unknown. This study reports the structure of the MHC-like molecule MR1 in complex with the vitamin B9-like protein pterin. Bacterial vitamin B derivatives are shown to activate MAIT cells, suggesting that the elusive antigens for MAIT cells are microbial vitamin metabolites and that the physiological role of these cells is to detect microbial infections.

Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called \"type 2 immune response,\" which confers protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli.

Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal—but not adult—GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.

Where is thy STING? The adaptor protein STING ('stimulator of interferon genes', also known as MITA and ERIS) is emerging as an important component of the innate immune system's response to microbial DNA. Ishikawa et al . show that in the absence of STING the sensitivity of mice to infection by several DNA and RNA viruses is enhanced. STING-mediated interferon induction requires STING to relocalize with TANK-binding kinase 1 from the endoplasmic reticulum to Sec5-containing endosome vesicles. This work implies that STING is essential for host defence against DNA pathogens such as herpes simplex virus. Although the innate immune system is known to be critical for the early detection of invading pathogens and for initiating host defence systems, little is known about how it is galvanized to respond to DNA-based microbes. STING (stimulator of interferon genes) is now shown to be necessary for the initiation of effective type I interferon production and, accordingly, there is an increase in the susceptibility of Sting -knockout mice to infection by the DNA virus HSV-1. The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN) 1 , 2 , 3 . However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection 4 . Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes ), were found to require STING to initiate effective IFN production. Accordingly, Sting -knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting -deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.

CD4⁺ T regulatory cells (Tregs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, Tregs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium, promoted Treg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor-β and affected Foxp3⁺ Treg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.

Mature B cells encounter antigens during development that induce anergy or functional unresponsiveness; this large reservoir of dormant autoreactive B cells may serve as a pool of extended antibody specificity for purposes of protective immunity, as well as the source of pathogenic autoantibodies that characterize rheumatic diseases such as systemic lupus erythematosus. Autoantigens and B-cell development This study demonstrates that B cells encounter autoantigens during development and that autoreactive B cells persist in the mature repertoire, but become less responsive or anergic to B-cell antigen-receptor stimulation, thereby avoiding autoimmunity. Autoreactivity seems to correlate with the threshold of B-cell activation so that only foreign antigens interacting with B cells at a level greater than the cells' inherent autoreactivity will be activated. The authors speculate that this large reservoir of dormant autoreactive B cells may act as a source of pathogenic autoantibodies in rheumatic diseases such as systemic lupus erythematosus. In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity 1 . Yet, how B cells establish and maintain tolerance in the face of autoantigen exposure during and after development is not certain. Studies of model B-cell antigen receptor (BCR) transgenic systems have highlighted the critical role of functional unresponsiveness or ‘anergy’ 2 , 3 . Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance 4 , 5 . However, it remains unclear whether the mature diverse B-cell repertoire of mice contains anergic autoreactive B cells, and if so, whether antigen was encountered during or after their development. By taking advantage of a reporter mouse in which BCR signalling rapidly and robustly induces green fluorescent protein expression under the control of the Nur77 regulatory region, antigen-dependent and antigen-independent BCR signalling events in vivo during B-cell maturation were visualized. Here we show that B cells encounter antigen during development in the spleen, and that this antigen exposure, in turn, tunes the responsiveness of BCR signalling in B cells at least partly by downmodulating expression of surface IgM but not IgD BCRs, and by modifying basal calcium levels. By contrast, no analogous process occurs in naive mature T cells. Our data demonstrate not only that autoreactive B cells persist in the mature repertoire, but that functional unresponsiveness or anergy exists in the mature B-cell repertoire along a continuum, a fact that has long been suspected, but never yet shown. These results have important implications for understanding how tolerance in T and B cells is differently imposed, and how these processes might go awry in disease.

Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.