Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway

Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promot...

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Bibliographic Details
Published in:Mucosal immunology 2015-01, Vol.8 (1), p.80-93
Main Authors: Park, J, Kim, M, Kang, S G, Jannasch, A H, Cooper, B, Patterson, J, Kim, C H
Format: Article
Language:English
Subjects:
Acetates - administration & dosage
Animals
Cell Differentiation - drug effects
Cell Differentiation - genetics
Cellular Microenvironment
Citrobacter rodentium - immunology
Citrobacter rodentium - metabolism
Enterobacteriaceae Infections - immunology
Enterobacteriaceae Infections - microbiology
Fatty Acids, Volatile - immunology
Histone Deacetylases - metabolism
Immune Tolerance
Immunity, Innate
Interferon-gamma - metabolism
Interleukin-10 - genetics
Interleukin-10 - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Signal Transduction
T-Lymphocytes, Regulatory - immunology
Th1 Cells - immunology
Th17 Cells - immunology
TOR Serine-Threonine Kinases - metabolism
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Summary:Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.
ISSN:1933-0219
1935-3456
DOI:10.1038/mi.2014.44