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Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10–producing regulatory B cells
Yoshiyuki Mishima, … , Christopher L. Karp, R. Balfour Sartor
Yoshiyuki Mishima, … , Christopher L. Karp, R. Balfour Sartor
Published June 18, 2019
Citation Information: J Clin Invest. 2019;129(9):3702-3716. https://doi.org/10.1172/JCI93820.
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Research Article Gastroenterology Immunology

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

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Abstract

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.

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

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Figure 5

Bacterial products predominantly expand GFP+ B cells and innate immune cells ex vivo.

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Bacterial products predominantly expand GFP+ B cells and innate immune c...
Unfractionated colonic LP cells from GF Il10+/EGFP reporter mice were cultured without (–, media only) or with 200 ng/mL LPS, 50 ng/mL Pam3csk (Pam), 1 nM CpG-DNA (CpG), 10 μg/mL lysates of E. coli LF82 (Ec), E. faecalis (Ef), or R. gnavus (Rg) or a mixture of 17 strains of Clostridia species (Clo). (A) Frequencies of GFP-expressing cell types were determined by flow cytometry using antibodies to cell surface markers as described in Methods. Data are presented as median of 4 separate cell cultures, with cells in each culture pooled from 2–4 mice; *P < 0.05, **P < 0.01, ***P < 0.001 (vs. no stimulation), Kruskal-Wallis test with Dunn’s post hoc test. (B) Representative dot plots for GFP (IL-10)+ B cells stimulated with or without CpG or Pam3. (C) Summary pie charts for cell populations expressing GFP.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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