The polycomb repressive complex 2 governs life and death of peripheral T cells

Blood. 2014 Jul 31;124(5):737-49. doi: 10.1182/blood-2013-12-544106. Epub 2014 Jun 20.

Abstract

Differentiation of naïve CD4(+) T cells into effector (Th1, Th2, and Th17) and induced regulatory (iTreg) T cells requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. The epigenetic silencing of cytokine genes is associated with the repressive H3K27 trimethylation mark, mediated by the Ezh2 or Ezh1 methyltransferase components of the polycomb repressive complex 2 (PRC2). Here we show that silencing of the Ifng, Gata3, and Il10 loci in naïve CD4(+) T cells is dependent on Ezh2. Naïve CD4(+) T cells lacking Ezh2 were epigenetically primed for overproduction of IFN-γ in Th2 and iTreg and IL-10 in Th2 cells. In addition, deficiency of Ezh2 accelerated effector Th cell death via death receptor-mediated extrinsic and intrinsic apoptotic pathways, confirmed in vivo for Ezh2-null IFN-γ-producing CD4(+) and CD8(+) T cells responding to Listeria monocytogenes infection. These findings demonstrate the key role of PRC2/Ezh2 in differentiation and survival of peripheral T cells and reveal potential immunotherapeutic targets.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Cell Differentiation / immunology*
  • Cell Survival / immunology
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Gene Silencing / immunology*
  • Humans
  • Interferon-gamma / immunology
  • Interleukin-10 / immunology
  • Listeria monocytogenes / immunology
  • Listeriosis / immunology
  • Listeriosis / pathology
  • Male
  • Mice
  • Polycomb Repressive Complex 2 / immunology*
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • IFNG protein, human
  • IL10 protein, human
  • Interleukin-10
  • Interferon-gamma
  • EZH1 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh1 protein, mouse
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2