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The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

The intestinal mucosa serves both as a conduit for the uptake of food-derived nutrients and microbiome-derived metabolites, and as a barrier that prevents tissue invasion by microorganisms and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here we show in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type-3 innate lymphoid cells (ILC3).sup.1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP).sup.4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; also known as VPAC2). Production of interleukin (IL)-22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria.sup.5-7, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased.sup.8. During food consumption, the activation of VIPergic neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL-22 and the efficiency of nutrient absorption. Modulation of this pathway may therefore be effective for enhancing resistance to enteropathogens.sup.2,3,9 and for the treatment of metabolic diseases. Feeding controls a neuroimmune circuit comprising VIP-producing neurons and type-3 innate lymphoid cells that helps to regulate the efficiency of nutrient uptake and IL-22-mediated immune protection in the intestine., Author(s): Jhimmy Talbot [sup.1] , Paul Hahn [sup.1] , Lina Kroehling [sup.1] , Henry Nguyen [sup.1] , Dayi Li [sup.1] , Dan R. Littman [sup.1] [sup.2] Author Affiliations: (1) Molecular [...]

In the mucosa, the immune system's T cells and B cells have position-specific phenotypes and functions that are influenced by the microbiota. These cells play pivotal parts in the maintenance of immune homeostasis by suppressing responses to harmless antigens and by enforcing the integrity of the barrier functions of the gut mucosa. Imbalances in the gut microbiota, known as dysbiosis, can trigger several immune disorders through the activity of T cells that are both near to and distant from the site of their induction. Elucidation of the mechanisms that distinguish between homeostatic and pathogenic microbiota-host interactions could identify therapeutic targets for preventing or modulating inflammatory diseases and for boosting the efficacy of cancer immunotherapy., Microbiotas that establish mutualistic relationships with their mammalian hosts are able to influence a multitude of physiological functions, often through modulation of the host's immune system. Certain bacteria that inhabit [...]

T helper 17 ([T.sub.H]17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective [T.sub.H]17 genes, and is required for [T.sub.H]17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in [T.sub.H]17-dependent diseases., [T.sub.H]17 cells are [CD4.sup.+] lymphocytes that help to protect mucosal epithelial barriers against bacterial and fungal infections (1), and are also important in multiple autoimmune diseases (2-7). The [T.sub.H]17 cell [...]

T-helper-17 ([T.sub.H]17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis (1-3). They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota (4-7). Segmented filamentous bacteria (SFB) are sufficient to induce [T.sub.H]17 cells and to promote [T.sub.H]17-dependent autoimmune disease in animal models (8-14). However, the specificity of [T.sub.H]17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal [T.sub.H]17 cells in SFB-colonized mice has minimal overlap with that of other intestinal [CD4.sup.+] T cells and that most [T.sub.H]17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing [T.sub.H]17 cells, even if SFB-colonized mice also harboured a strong [T.sub.H]1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines., How SFB induces [T.sub.H]17 cells and how these cells contribute to self-reactive pathological responses remain key unanswered questions. A recent study, using mice with monoclonal TCRs, suggested that induction of [...]

Author(s): Mo Xu [1]; Maria Pokrovskii [1]; Yi Ding [2]; Ren Yi [3]; Christy Au [1, 4]; Oliver J. Harrison [5]; Carolina Galan [1]; Yasmine Belkaid [5, 6]; Richard Bonneau [...]

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial [...]

[CD4.sup.+] T helper lymphocytes that express interleukin-17 ([T.sub.H]17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in [T.sub.H]17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis (1-3). Thus, the pathway towards differentiation of [T.sub.H]17 cells and, perhaps, of related innate lymphoid cells with similar effector functions (4,5), is an attractive target for therapeutic applications. Mouse and human [T.sub.H]17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of TH17-dependent autoimmune disease in mice (6). By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine [T.sub.H]17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin21-salicylidene specifically inhibited induction of IL-17 in human [CD4.sup.+] T cells. Using these small-molecule compounds, we demonstrate that RORγt is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease., To identify small molecules that specifically inhibit transcriptional activity of RORγ and RORγt isoforms, we prepared Drosophila S2 cells stably expressing fusions of the GAL4 DNA-binding domain (DBD) and the [...]

Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses (1,2). Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known (3). Dendritic cells are largely resistant to infection with HIV-1 (4), but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement (5,6). Here we show that, when dendritic cell resistance to infection is circumvented (7,8), HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine., The exposure of monocyte-derived dendritic cells (MDDCs) to GFP-encoding HIV-1 pseudotyped with vesicular stomatitis virus protein G (VSV-G) (hereafter referred to as HIV-GFP(G); multiplicity of infection (MOI) 1-2, see Supplementary [...]

Innate intestinal inflammatory responses Interleukin 23 (IL-23) has been implicated in the pathogenesis of autoimmune and chronic inflammatory disorders. New work in a mouse model has identified a previously unrecognized population of innate lymphoid cells that respond to IL-23 by inducing inflammation through the production of IL-17 and interferon-[gamma]. Further work will be needed to establish whether this newly discovered IL-23-driven pathway contributes to chronic inflammatory diseases such as irritable bowel disease. The cytokine interleukin (IL)-23 has inflammatory effects on innate immune cells and can drive colitis, but the cellular and molecular pathways involved are poorly characterized. Here it is shown that bacterial-driven innate colitis involves a previously unknown population of IL-23-responsive innate leukocytes that produce IL-17 and interferon-[gamma]. These cells may represent a target in inflammatory bowel disease. The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (T.sub.H17) cells.sup.1. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells.sup.2 and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-[gamma] in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-[gamma] exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-[gamma]t and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-[gamma]t, which controls IL-23R expression, has a functional role, because Rag.sup.-/-Rorc.sup.-/- mice failed to develop innate colitis. Last, depletion of Thy1.sup.+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease., Author(s): Sofia Buonocore [sup.1] , Philip P. Ahern [sup.1] , Holm H. Uhlig [sup.3] , Ivaylo I. Ivanov [sup.4] , Dan R. Littman [sup.4] , Kevin J. Maloy [sup.1] , [...]

Thelper cells that produce IL-17 ([T.sub.H]17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, [T.sub.H]17 cells are thought to [...]

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation., Author(s): Yeong Shin Yim [1, 2]; Ashley Park [1, 2]; Janet Berrios [1, 2]; Mathieu Lafourcade [1, 2]; Leila M. Pascual [1, 2]; Natalie Soares [1, 2]; Joo Yeon Kim [...]

Author(s): Tian H. Chi [1]; Mimi Wan [1]; Keji Zhao [2]; Ichiro Taniuchi [3]; Lei Chen [1]; Dan R. Littman [3]; Gerald R. Crabtree (corresponding author) [1] Thymic development produces [...]

Author(s): Zuoming Sun [1]; Christopher W. Arendt [1]; Wilfried Ellmeier [1, 2]; Edward M. Schaeffer [3, 4]; Mary Jean Sunshine [1, 2]; Leena Gandhi [1]; Justin Annes [1]; Daniela Petrzilka [...]

CXCR4, a chemokine receptor, is expressed in cells of the immune and central nervous systems, and can control migration of resting leukocytes and haematopoietic progenitors. Mice lacking CXCR4 were found to show haematopoietic and cardiac defects the same as those of SDF-1-deficient mice, suggesting that it may be the only receptor for SDf-1. This is thought to be the first demonstration of G-protein-coupled chemokine receptor involvement in neuronal cell migration and patterning in the central nervous system.

Several types of chemokine-receptors together with CD4, act as receptors for entry of human immunodeficiency virus type I into cells. Infection with some strains of simian immunodeficiency virus (SIV) is mediated by CCR5. An expression cloning strategy is used to identify SIV receptors, isolating genes in the seven-transmembrane G-protein, possibly providing an insight into viral transmission.

The CC-CRK-5 beta-chemokine receptor functions as a co-receptor for the primary macrophage-trophic strains of the human immunodeficiency virus 1 (HIV-1) and acts along with CD4 to enable the entry of the virus into host cells. Cells co-expressing CD4 and CC-CRK-5 are highly susceptible to HIV infection while those co-expressing CD4 and other members of the CC-CRK-5 family are resistant to infection. CC-CRK-5 activates the fusion of plasma membrane with the HIV-1 envelope. Beta-chemokines are cytokines that suppress HIV infection by blocking its entry and replication in cells.

Researchers are tracing the part played by CD4-p56lck association during the progress of the t-lymphocyte. The glycoproteins CD4 and CD8 interact with protein tyrosine kinase (PTK) p56lck, which is important for thymocyte maturation and activating T-cells. Although CD4 cannot relate with p56lck, it can aid the helper-cell lineage when over expressed. Several experiments have proved that CD4 and CD8 are essential for T-cell lineage determination, because of their transducing properties, and that CD4 can work without the help of p56lck in T-cell development. The PTK, with which CD4 is associated, does not seem important in picking the helper T-cell lineage.

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells. Screening of a library of bile acid metabolites revealed two derivatives of lithocholic acid that act as regulators of T helper cells that express IL-17a and regulatory T cells, thus influencing host immune responses. [ABSTRACT FROM AUTHOR]

A mutation in the CC-chemokine receptor 5 (CCR-5) prevents HIV infection despite repeated exposure to the infection. Homozygous mutants of the gene are found in HIV resistant people. HIV-infected individuals have a lower frequency of heterozygous CCR-5 mutants. This indicates a partial protection from HIV infection in individuals with a single mutant gene. Individuals without functional CCR-5 are immunologically well.

T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4+ T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines. [ABSTRACT FROM AUTHOR]

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX3CR1hi mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX3CR1hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation. [ABSTRACT FROM AUTHOR]

CD4+ T helper lymphocytes that express interleukin-17 (TH17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in TH17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of TH17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human TH17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of TH17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine TH17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4+ T cells. Using these small-molecule compounds, we demonstrate that RORγt is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease. [ABSTRACT FROM AUTHOR]

T helper cells that produce IL-17 (TH17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, TH17 cells are thought to protect the host from infection, whereas regulatory T (Treg) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-β (TGF-β), but depends on distinct transcription factors: RORγt (encoded by Rorc(γt)) for TH17 cells and Foxp3 for Treg cells. How TGF-β regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-β orchestrates TH17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-β synergizes with interleukin (IL)-6 and IL-21 (refs 9–11) to promote IL-23 receptor (Il23r) expression, favouring TH17 cell differentiation. High concentrations of TGF-β repress IL23r expression and favour Foxp3+ Treg cells. RORγt and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-β and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-β-induced Foxp3 inhibits RORγt function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORγt alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORγt, thereby promoting TH17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either TH17 or Treg cells depends on the cytokine-regulated balance of RORγt and Foxp3. [ABSTRACT FROM AUTHOR]