Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10–producing regulatory B cells

• DOI: 10.1172/jci93820
• Publication Date: 2019-06-18T16:01:22Z
• Authors: Yoshiyuki Mishima; Akihiko Oka; Bo Liu; Jeremy W. Herzog; Chang Soo Eun; Ting-Jia Fan; Emily Bulik-Sullivan; Ian M. Carroll; Jonathan J. Hansen; Liang Chen; Justin E. Wilson; Nancy C. Fisher; Jenny P.Y. Ting; Tomonori Nochi; Angela Wahl; J. Victor Garcia; Christopher L. Karp; R. Balfour Sartor
• Keywords: Inflammation; Mice, Knockout; 0301 basic medicine; B-Lymphocytes, Regulatory; Green Fluorescent Proteins; Down-Regulation; Fecal Microbiota Transplantation; Colitis; Immunity, Innate; Toll-Like Receptor 2; Gastrointestinal Microbiome; Interleukin-10; 3. Good health; Intestines; Mice, Inbred C57BL; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Toll-Like Receptor 9; Myeloid Differentiation Factor 88; Animals; Cytokines; Germ-Free Life

Resident microbiota activates regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies describe the functional importance and mechanisms by which gut microbiota and specific microbial components influence the development of intestinal IL-10-producing B cells. Using fecal transplant into germ-free (GF) Il10+/EGFP reporter and Il10-/- mice, we demonstrated that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory 1 cells in ex-GF mice. IL-10 in turn downregulated microbiota-activated mucosal inflammatory cytokines. TLR2 and -9 ligands and enteric bacterial lysates preferentially induced IL-10 production and the regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell cotransfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2-, MyD88-, and PI3K-dependent fashion. In vitro studies implicated downstream signaling of PI3Kp110δ and AKT. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88, and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.