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Innate PI3K p110? regulates Th1/Th17 development and microbiota-dependent colitis.

ABSTRACT: The p110? subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110? subunit (p110?(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110?(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110?(KD) mice. Colonic tissue and macrophages from p110?(KD) mice produce significantly less IL-10 compared with wild-type mice. p110?(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-?- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110?(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110?(KD) recipient mice develop severe colitis with increased percentages of IFN-?- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110? controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110? expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.

SUBMITTER: Steinbach EC

PROVIDER: S-EPMC3992276 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.

Steinbach Erin C EC Kobayashi Taku T Russo Steven M SM Sheikh Shehzad Z SZ Gipson Gregory R GR Kennedy Samantha T ST Uno Jennifer K JK Mishima Yoshiyuki Y Borst Luke B LB Liu Bo B Herfarth Hans H Ting Jenny P Y JP Sartor R Balfour RB Plevy Scott E SE

Journal of immunology (Baltimore, Md. : 1950) 20140314 8

The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly ...[more]

PMID: 24634494

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Project description:BACKGROUND:How the gut microbiota regulates intestinal homeostasis is not completely clear. Gut microbiota metabolite short-chain fatty acids (SCFAs) have been reported to regulate T-cell differentiation. However, the mechanisms underlying SCFA regulation of T-cell differentiation and function remain to be investigated. METHODS:CBir1, an immunodominant microbiota antigen, transgenic T cells were treated with butyrate under various T-cell polarization conditions to investigate butyrate regulation of T-cell differentiation and the mechanism involved. Transfer of butyrate-treated CBir T cells into Rag1-/- mice was performed to study the in vivo role of such T cells in inducing colitis. RESULTS:Although butyrate promoted Th1 cell development by promoting IFN-? and T-bet expression, it inhibited Th17 cell development by suppressing IL-17, Ror?, and Ror?t expression. Interestingly, butyrate upregulated IL-10 production in T cells both under Th1 and Th17 cell conditions. Furthermore, butyrate induced T-cell B-lymphocyte-induced maturation protein 1 (Blimp1) expression, and deficiency of Blimp1 in T cells impaired the butyrate upregulation of IL-10 production, indicating that butyrate promotes T-cell IL-10 production at least partially through Blimp1. Rag1-/- mice transferred with butyrate-treated T cells demonstrated less severe colitis, compared with transfer of untreated T cells, and administration of anti-IL-10R antibody exacerbated colitis development in Rag-/- mice that had received butyrate-treated T cells. Mechanistically, the effects of butyrate on the development of Th1 cells was through inhibition of histone deacetylase but was independent of GPR43. CONCLUSIONS:These data indicate that butyrate controls the capacity of T cells in the induction of colitis by differentially regulating Th1 and Th17 cell differentiation and promoting IL-10 production, providing insights into butyrate as a potential therapeutic for the treatment of inflammatory bowel disease.

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Innate PI3K p110? regulates Th1/Th17 development and microbiota-dependent colitis.

Publications

Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.

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