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M2 Macrophages Drive the Production of Induced Regulatory T Cells in the Gut: P‐180

BACKGROUND: The microbiota is important in shaping the mammalian host’s immune system and is useful in identifying mechanisms of immune maturation. In the limited number of associations between commensal microbes and the immune system that are known to indicate a profound immunomodulatory relationship, the microbes involved have been identified at the genus (or sometimes the species) level; in contrast, little relevant information has been obtained at the microbial molecular level. A notable exception is the relationship between capsular polysaccharide A (PSA) of the gut commensal Bacteroides fragilis and the induction of regulatory T cells (Tregs) that can limit pathologic inflammation both in the gut and in more distant tissues. The ability of PSA to induce secretion of the potent anti-inflammatory cytokine interleukin 10 (IL-10) is vital to the control of inflammation. Restoration of tissue homeostasis by a functional class of dendritic cells (DCs), designated tolerogenic DCs, has been described and is due, at least in part, to generation or enhancement of the function of Tregs. Although PSA affects DCs, it has not been shown whether DCs play a role in the immunoregulatory activities of PSA. METHODS: We treated specific-pathogen-free animals with B fragilis expressing PSA and followed T regs and associated DCs in mesenteric lymph nodes and other tissues in absence of additional inflammatory stimulus. We purified PSA from B fragilis and utilized in vitro in DC-CD4þT cell co-culture assay and in vivo in TNBS-induced colitis and Myelin-PLP induced multiple sclerosis models. Genetically deficient mice, antibody mediated in vivo inhibition and depletion along with adoptive transfer of PSA treated DC subsets were employed. RESULTS: We show that a subset of DCs known as plasmacytoid DCs (PDCs) when exposed to PSA are potent inducers of IL-10 production by CD4þ T cells in vitro. In the murine model of colonic inflammation, PDCs characteristically phenotype PSA mediated protection in a Toll-like receptor 2 (TLR2) dependent way. Interestingly, PDCs are essential for the immunoprotective activities of PSA in this colitis model as observed by antibody mediated PDC depletion and adoptive transfer experiments. TLR2, an immunosensitive receptor of PSA, is induced in PDCs by PSA and, along with ICOSL and CD86, mediates PSA’s immunoregulatory function in vitro and in vivo. Finally, in a murine model of multiple sclerosis wherein PSA was found to be protective, we observed near complete mortality in mice treated with PDC depleting antibody irrespective of PSA treatment, while the isotype control treated mice survived and were protected significantly by PSA treatment in terms of clinical scores. CONCLUSION(S): Our results demonstrate how a prototypical molecule from the commensal microbiota enables a subset of DCs to modify pathologic outcome in the gut and a distant tissue. Understanding functional polarization of PDCs or other DCs by molecules derived from the commensal microbiota and elucidating how these molecules shape immune development may help identify new therapeutic approaches to inflammatory diseases.