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The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.

A T cell receptor transgenic mouse line reactive to a microbiota flagellin, CBir1, was used to define mechanisms of host microbiota homeostasis. Intestinal IgA, but not serum IgA, was found to block mucosal flagellin uptake and systemic T cell activation in mice. Depletion of CD4⁺CD25⁺ Tregs decreased IgA⁺ B cells, total IgA, and CBir1-specific IgA in gut within days. Repletion of T cell-deficient mice with either CD4⁺CD25⁺ or CD4⁺foxp3⁺ Tregs restored intestinal IgA to a much greater extent than their reciprocal CD4⁺ subsets, indicating that Tregs are the major helper cells for IgA responses to microbiota antigens such as flagellin. We propose that the major role of this coordinated Treg-IgA response is to maintain commensalism with the microbiota.

The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity.

The intestinal microbiota is critical for maintaining homeostasis. Dysbiosis, an imbalance in the microbial community, contributes to the susceptibility of several diseases. Many factors are known to influence gut microbial composition, including diet. We have previously shown that fecal immunoglobulin (Ig) A levels are decreased in mice fed a diet free of aryl hydrocarbon receptor (AhR) ligands. Here, we hypothesize this IgA decrease is secondary to diet-induced dysbiosis. We assigned mice to a conventional diet, an AhR ligand-free diet, or an AhR ligand-free diet supplemented with the dietary AhR ligand indole-3-carbinol (I3C). We observed a global alteration of fecal microbiota upon dietary AhR ligand deprivation. Compared to mice on the conventional diet, family Erysipelotrichaceae was enriched in the feces of mice on the AhR ligand-free diet but returned to normal levels upon dietary supplementation with I3C. Faecalibaculum rodentium , an Erysipelotrichaceae species, depleted its growth media of AhR ligands. Cultured fecal bacteria from mice on the AhR ligand-free diet, but not the other two diets, were able to alter IgA levels in vitro , as was F . rodentium alone. Our data point to the critical role of AhR dietary ligands in shaping the composition and proper functioning of gut microbiota.

Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD). One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg)- Immunoglobulin A (IgA) pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB) via the A2 linker of CT. Both dendritic cells (DCs) and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA) signaling but was inhibited by neutralization of TGF-β. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR) signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.

Toll-like receptor (TLR) 5 has been shown to maintain intestinal homeostasis and regulate host defense against enterobacterial infection. However, how TLR5 expression is regulated and its function in the intestine have not been fully elucidated. Here we demonstrate that mucosal dendritic cells (DCs), but not splenic DCs, express high levels of TLR5 protein. Alternatively spliced Tlr5 transcripts were identified but it did not explain the selective expression of TLR5 on mucosal DCs. Treatment with various bacterial ligands downregulated BMDC TLR5 expression, while retinoic acid and host stromal cell-derived signals promoted TLR5 expression in a TGF-β-independent mechanism. Signaling through TLR5 restrained regulatory T (Treg) cell generation, and accordingly, TLR5(-/-) mice displayed increased frequencies of Foxp3(+) Treg cells in the intestinal lamina propria. Our data indicate that bacterial and host factors differentially regulate DC TLR5 expression. TLR5 signaling regulates immune responses towards the microbiota via modulation of the Treg/effector T cell balance.

Over 30 years ago, Rutgeerts et al published a seminal paper detailing the endoscopic recurrence of Crohn’s disease in the neoterminal ileum following ileocecal resection.1 The eponymous Rutgeerts scoring scale in that paper has been widely adopted and remains in wide clinical use today. The ability to directly visualise recurrent lesions prior to any symptoms or radiologic abnormalities has changed practice. Ileocolonoscopy within the first year after ileocecal or ileocolonic resection to assess recurrence and the Rutgeerts score is now standard of care (table 1). Crohn’s disease recurrence is frequent but not universal and progresses over months to years, enough time to intervene, assuming an effective therapy. Indeed monoclonal anti-TNF therapy has shown some ability to halt or prevent recurrence. However, even in this era of biological therapy, recurrence of Crohn’s disease remains high, afflicting half or more patients after surgery. A better understanding of the sequence of events and pathogenesis of ileal tissue lesions is needed to better target therapies to prevent recurrence.

Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.

Over the past decade, emerging evidence has linked alterations in the gut microbial composition to a wide range of diseases including obesity, type 2 diabetes, and cardiovascular disease. Toll-like receptors (TLRs) are the major mediators for the interactions between gut microbiota and host innate immune system, which is involved in the localization and structuring of host gut microbiota. A previous study found that TLR5 deficient mice (TLR5KO1) had altered gut microbial composition which led to the development of metabolic syndrome including hyperlipidemia, hypertension, insulin resistance and increased adiposity. In the current study, a second TLR5-deficient mouse model was studied (TLR5KO2). TLR5 deficient mice did not manifest metabolic abnormalities related to the metabolic syndrome compared with littermate controls maintained on normal chow or after feeding a high fat diet. Analysis of the gut microbial composition of littermate TLR5KO2 and wild type mice revealed no significant difference in the overall microbiota structure between genotypes. However, the TLR5KO2 microbiota was distinctly different from that previously reported for TLR5KO1 mice with metabolic syndrome. We conclude that an altered composition of the microbiota in a given environment can result in metabolic syndrome, but it is not a consequence of TLR5 deficiency per se.

HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.