Commensal polysaccharide-induced T cell communication and peripheral immune regulation

The increasing prevalence of inflammatory and autoimmune diseases across the world has been attributed in part to a shift in microbial exposure both in the exogenous environment and the endogenous microbiome. Here we identify and adopt a strategy used by a common commensal gut microbe, Bacteroides fragilis, to suppress inappropriate immune activation. Bacteroides fragilis produces a protective capsule containing polysaccharide A (PSA), which has been shown to suppress a host of inflammatory diseases in an IL-10-dependent manner. We have discovered that PSA is endocytosed, processed, and presented by APCs through MHCII and αβTCR engagement, and clonally expands CD4+FoxP3−CD25−CD45Rblo cells of an effector memory subset (RbloTEM). RbloTEM are capable of suppressing peripheral inflammation in way dependent on IL-10, however, they themselves do not produce the IL-10 necessary for suppression of disease. We show here that RbloTEM cells communicate directly with FoxP3+ Regulatory T cells, resulting in enhanced IL-10 production. Using novel FoxP3RFP/IL-10GFP dual reporter mice, we further demonstrate that this communication induces synergistic IL-10 expression specifically in Tregs, enhances Treg proliferation, and drives Treg-mediated immune inhibition by preferentially favoring the expansion of IL-10+ Tregs. Through promoting a robust and rapid Treg response, we show that the cytokine signature of PSA-responding RbloTEM cells and coordinating FoxP3+ Tregs can suppress mouse models of inflammatory disease, including HDM-induced asthma and EAE.