Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells

J Exp Med. 2020 Jul 6;217(7):e20191453. doi: 10.1084/jem.20191453.

Abstract

Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program.

Publication types

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

MeSH terms

  • Acetylation / drug effects
  • Acrylamides / pharmacology
  • Animals
  • Antigens / metabolism
  • Base Sequence
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • Epigenesis, Genetic* / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / deficiency
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Lymph Nodes / drug effects
  • Lymph Nodes / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphocytic choriomeningitis virus / physiology
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Phenylenediamines / pharmacology
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism
  • T-Lymphocytes, Cytotoxic* / drug effects
  • Transcription, Genetic / drug effects

Substances

  • Acrylamides
  • Antigens
  • Core Binding Factor Alpha 3 Subunit
  • Histone Deacetylase Inhibitors
  • Histones
  • Phenylenediamines
  • Prdm1 protein, mouse
  • RGFP966
  • Positive Regulatory Domain I-Binding Factor 1
  • Histone Deacetylases
  • histone deacetylase 3
  • Lysine