Journal Article

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

Wilson, Justin E., Oka, Akihiko, Wahl, Angela, Fisher, Nancy C., Chen, Liang, Mishima, Yoshiyuki, Garcia, J. Victor, Nochi, Tomonori, Bulik-Sullivan, Emily, Sartor, R. Balfour, Liu, Bo, Karp, Christopher L., Carroll, Ian M., Fan, Ting-Jia, Herzog, Jeremy W., Eun, Chang Soo, Ting, Jenny P.Y., Hansen, Jonathan J.

2019

Overview

Resident microbiota activate regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies described the functional importance and mechanisms by which gut microbiota and specific microbial components influenced the development of intestinal IL-10-producing B cells. We used fecal transplant to germ-free (GF) Il10+/EGFP reporter and Il10-/- mice to demonstrate 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 down-regulated microbiota-activated mucosal inflammatory cytokines. TLR2/9 ligands and enteric bacterial lysates preferentially induced IL-10 production and regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell co-transfer 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 PI3Kp110δ and AKT downstream signaling. 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.

• Publisher: American Society for Clinical Investigation
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Analysis / Antigens / B cells / Bacteria / Bacterial infections / Biomedical research / Cell activation / Colitis / Colon / Consortia / Crohn's disease / Cytokines / Gastroenterology / Genes / Genetic research / Germfree / Homeostasis / House mouse / Immunoregulation / Inflammation / Inflammatory bowel disease / Interleukin 1 / Interleukin 10 / Intestinal microflora / Intestine / Journalists / Kinases / Lymphocytes / Lymphocytes B / Lymphocytes T / Lysates / Microbiota / Microbiota (Symbiotic organisms) / Mucosa / MyD88 protein / Pathogenesis / Regulation / Scientific equipment industry / T cells / TLR2 protein / Toll-like receptors