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

Mucosal Immunol. 2015 Jan;8(1):80-93. doi: 10.1038/mi.2014.44. Epub 2014 Jun 11.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • TOR Serine-Threonine Kinases / metabolism*
  • Th1 Cells / immunology
  • Th17 Cells / immunology

Substances

  • Acetates
  • Fatty Acids, Volatile
  • Interleukin-10
  • Interferon-gamma
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Histone Deacetylases