Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4(+) T Cells

Immunity. 2016 Jun 21;44(6):1337-49. doi: 10.1016/j.immuni.2016.05.009. Epub 2016 Jun 14.

Abstract

Distinct metabolic programs support the differentiation of CD4(+) T cells into separate functional subsets. In this study, we investigated metabolic mechanisms underlying the differentiation of IL-9-producing CD4(+) T cells (Th9) in allergic airway inflammation and cancerous tumors. We found that histone deacetylase SIRT1 negatively regulated Th9 cell differentiation. A deficiency of SIRT1 induced by either conditional deletion in mouse CD4(+) T cells or the use of small interfering RNA (siRNA) in mouse or human T cells increased IL-9 production, whereas ectopic SIRT1 expression inhibited it. Notably, SIRT1 inhibited Th9 cell differentiation that regulated anti-tumor immunity and allergic pulmonary inflammation. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF1α) was required for the differentiation of Th9 cells that conferred protection against tumors and is involved in allergic airway inflammation. Our results define the essential features of SIRT1-mTOR-HIF1α signaling-coupled glycolytic pathway in inducing Th9 cell differentiation, with implications for metabolic reprogramming as an immunotherapeutic approach.

Keywords: SIRT1; T cell differentiation; Th9 cells; allergic airway inflammation; glycolysis; metabolism; tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Glycolysis
  • Humans
  • Hypersensitivity / immunology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interleukin-9 / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Melanoma / immunology*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptional Activation

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-9
  • RNA, Small Interfering
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Sirt1 protein, mouse
  • Sirtuin 1