MyD88 Adaptor-Dependent Microbial Sensing by Regulatory T Cells Promotes Mucosal Tolerance and Enforces Commensalism

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 2; pp. 289 - 303
• Main Authors: Wang, Sen, Charbonnier, Louis-Marie, Noval Rivas, Magali, Georgiev, Peter, Li, Ning, Gerber, Georg, Bry, Lynn, Chatila, Talal A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.08.2015; Elsevier Limited
• Subjects: Animals; Antibodies, Bacterial - metabolism; Antigens; Bacteria; Cell Differentiation; Cells, Cultured; Colitis - immunology; Drinking water; E coli; Escherichia coli - immunology; Escherichia coli Infections - immunology; Immune Tolerance; Immunity, Mucosal; Immunoglobulin A - metabolism; Inflammation; Inflammatory bowel disease; Intestines - immunology; Intestines - microbiology; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Rodents; STAT3 Transcription Factor - metabolism; Symbiosis - immunology; T cell receptors; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Toll-Like Receptors - metabolism
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2015.06.014

Commensal microbiota promote mucosal tolerance in part by engaging regulatory T (Treg) cells via Toll-like receptors (TLRs). We report that Treg-cell-specific deletion of the TLR adaptor MyD88 resulted in deficiency of intestinal Treg cells, a reciprocal increase in T helper 17 (Th17) cells and heightened interleukin-17 (IL-17)-dependent inflammation in experimental colitis. It also precipitated dysbiosis with overgrowth of segmented filamentous bacteria (SFB) and increased microbial loads in deep tissues. The Th17 cell dysregulation and bacterial dysbiosis were linked to impaired anti-microbial intestinal IgA responses, related to defective MyD88 adaptor- and Stat3 transcription factor-dependent T follicular regulatory and helper cell differentiation in the Peyer’s patches. These findings establish an essential role for MyD88-dependent microbial sensing by Treg cells in enforcing mucosal tolerance and maintaining commensalism by promoting intestinal Treg cell formation and anti-commensal IgA responses. [Display omitted] •MyD88 regulates gut Treg cell differentiation and stability in a cell-intrinsic manner•MyD88-Stat3 signaling in Treg cells directs the gut Tfh-Tfr-IgA axis•MyD88-dependent microbial sensing in Treg cells promotes commensalism through IgA•MyD88 signaling in Treg cells controls Th17 cell expansion by curtailing SFB growth Reciprocal interactions between the commensal flora and Treg cells promote immunological tolerance. Here, Wang et al. demonstrate that MyD88-Stat3-dependent microbial sensing by Treg cells enforces commensalism by directing gut anti-microbial IgA responses. Failure of this pathway results in the over-growth of pathobionts and dysregulation of pro-inflammatory Th17 cells.