Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

JCI Insight. 2020 Feb 27;5(4):e133393. doi: 10.1172/jci.insight.133393.


Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ-JAK1/2-STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus-infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.

Keywords: Immunology; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / drug effects
  • Cell Differentiation / physiology*
  • Fatty Acids / pharmacology
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / physiology*
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Signal Transduction / physiology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / physiology*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Fatty Acids
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2