Dataset Information

Regulation of the effector function of CD8⁺ T cells by gut microbiota-derived metabolite butyrate.

ABSTRACT: The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4⁺ T cells and antigen presenting cells. Here we show that butyrate and, to a lesser degree, propionate directly modulate the gene expression of CD8⁺ cytotoxic T lymphocytes (CTLs) and Tc17 cells. Increased IFN-? and granzyme B expression by CTLs as well as the molecular switch of Tc17 cells towards the CTL phenotype was mediated by butyrate independently of its interaction with specific SCFA-receptors GPR41 and GPR43. Our results indicate that butyrate strongly inhibited histone-deacetylases (HDACs) in CD8⁺ T cells thereby affecting the gene expression of effector molecules. Accordingly, the pan-HDAC inhibitors trichostatin A (TSA) and sodium valproate exerted similar influence on CD8⁺ T cells. Furthermore, higher acetate concentrations were also able to increase IFN-? production in CD8⁺ T lymphocytes by modulating cellular metabolism and mTOR activity. These findings might have significant implications in adoptive immunotherapy of cancers and in anti-viral immunity.

SUBMITTER: Luu M

PROVIDER: S-EPMC6158259 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulation of the effector function of CD8<sup>+</sup> T cells by gut microbiota-derived metabolite butyrate.

Luu Maik M Weigand Katharina K Wedi Fatana F Breidenbend Carina C Leister Hanna H Pautz Sabine S Adhikary Till T Visekruna Alexander A

Scientific reports 20180926 1

The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4<sup>+</sup> T cells and antigen presenting cells. Here we show that butyrate and, t ...[more]

PMID: 30258117

Similar Datasets

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.

Dataset Information

Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate.

Publications

Regulation of the effector function of CD8<sup>+</sup> T cells by gut microbiota-derived metabolite butyrate.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Regulation of the effector function of CD8⁺ T cells by gut microbiota-derived metabolite butyrate.