Inducible Foxp3 ⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota

Abstract

To maintain intestinal health, the immune system must faithfully respond to antigens from pathogenic microbes while limiting reactions to self-molecules. The gastrointestinal tract represents a unique challenge to the immune system, as it is permanently colonized by a diverse amalgam of bacterial phylotypes producing multitudes of foreign microbial products. Evidence from human and animal studies indicates that inflammatory bowel disease results from uncontrolled inflammation to the intestinal microbiota. However, molecular mechanisms that actively promote mucosal tolerance to the microbiota remain unknown. We report herein that a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3 + regulatory T cells (Tregs) with a unique "inducible" genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3 + T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4 + T cells into Foxp3 + Treg cells that produce IL-10 during commensal colonization. Functional Foxp3 + Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression. Most significantly, we show that PSA is not only able to prevent, but also cure experimental colitis in animals. Our results therefore demonstrate that B. fragilis co-opts the Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance.Bacteroides fragilis | inflammatory bowel disease | Toll-like receptor | polysaccharide A | interleukin 10

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

“…Certain Bacteriodetes species are already known to promote accumulation of Treg cells and has beside its anti-inflammatory properties also been found relatively more abundant in controls than human T1D children. 14,16 Significantly reduced abundance of Prevotella in diabetic patients was previously observed in prediabetic Finnish children 29 and recently confirmed in a cohort of Mexican children suffering from T1D 30 which supports its possible anti-inflammatory properties. In contrast, Oscillospira was negatively associated with diabetes development and low level of Treg cells.…”

“…Studies in germ-free and gnotobiotic mice have provided evidence that stimulation afforded by the immune recognition of microorganisms is required for both pro-and anti-inflammatory mechanisms to evolve. 15 The presence of Bacteroides fragiles, 16 probiotic Bifidobacterium infantis, 17 Lactobacillus reuteri, 18,19 and several Clostridium spp. in the gut 20 have for example been shown to increase the number and suppressive activity of regulatory T (Treg) cells; often associated with a decrease in proinflammatory cell numbers, pointing toward a profound effect of microbiota on immune homeostasis.…”

Microbiota of De-Novo Pediatric IBD: Increased Faecalibacterium Prausnitzii and Reduced Bacterial Diversity in Crohn's But Not in Ulcerative Colitis

“…Our data directly contradict this hypothesis. One possible explanation might be highlighted by Bacteroides fragilis , an organism found to be capable of initiating colitis in animal models ( 36 ), but also of directing an anti-infl ammatory immune response ( 37,38 ). Individual components of the microbiota may thus fulfi ll diff ering roles under diff erent conditions.…”

CD4+ T cells from multiple sclerosis patients respond to a commensal‐derived antigen

“…Orally administered PSA protects against EAE and experimental colitis by eliciting T regs with IL‐10‐dependent immunosuppressive function 12, 13. While it had previously been demonstrated that PSA acts via TLR2 to drive the induction of T regs in mice,14 we have recently shown that PSA can induce the differentiation of T regs when added to in vitro co‐cultures of dendritic cells (DCs) and naïve T cells isolated from the blood of healthy donors 15. In this study, we determined if PSA could similarly drive the differentiation of T regs from naïve T cells isolated from patients with MS.…”