The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation

J Immunol. 2017 May 15;198(10):3927-3938. doi: 10.4049/jimmunol.1600312. Epub 2017 Apr 19.

Abstract

Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production, and Th1/Th17, but not Th2 and regulatory T cell differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the NFAT in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 acetylation to promote IL-2 production. T cell-specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence Gcn5 may be an important new target for autoimmune disease therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Gene Expression Regulation
  • Histone Acetyltransferases / deficiency
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Interleukin-2 / deficiency
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Lymphocyte Activation*
  • Mice
  • NFATC Transcription Factors / genetics
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Processing, Post-Translational
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / physiology
  • Th1 Cells / immunology
  • Th1 Cells / physiology
  • Th2 Cells / immunology
  • Th2 Cells / physiology

Substances

  • Interleukin-2
  • NFATC Transcription Factors
  • GCN5 histone acetyltransferase, mouse
  • Histone Acetyltransferases