title: Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway.
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.
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, West Lafayette, Indiana, USA.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, West Lafayette, Indiana, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kim
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, West Lafayette, Indiana, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Metabolite Profiling Facility, Bindley Bioscience Center, West Lafayette, Indiana, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Jannasch
authors.affiliation: Metabolite Profiling Facility, Bindley Bioscience Center, West Lafayette, Indiana, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cooper
authors.affiliation: Department of Animal Science, West Lafayette, Indiana, USA.
authors.forename: J
authors.initials: J
authors.lastname: Patterson
authors.affiliation: 1] Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, West Lafayette, Indiana, USA [2] Weldon School of Biomedical Engineering, West Lafayette, Indiana, USA [3] Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000085:Acetates / Q000008:administration & dosage; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D060833:Cellular Microenvironment; D044082:Citrobacter rodentium / Q000276:immunology / Q000378:metabolism*; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000382:microbiology; D005232:Fatty Acids, Volatile / Q000276:immunology*; D006655:Histone Deacetylases / Q000378:metabolism*; D007108:Immune Tolerance; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D000085:Acetates; D005232:Fatty Acids, Volatile; D016753:Interleukin-10; D007371:Interferon-gamma; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases