Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8 + T Cell Terminal Differentiation and Loss of Multipotency

Immunity. 2017 Apr 18;46(4):596-608. doi: 10.1016/j.immuni.2017.03.012. Epub 2017 Apr 11.

Abstract

Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8+ T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2 deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8+ memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, probably from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic silencing of pro-memory genes in effector T cells.

Keywords: CD8(+) T cell differentiation; EZH2; FOXO1; H3K27ac; H3K27me3; PRC2; Polycomb repressive complex 2; epigenetics; plasticity; terminal differentiation.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Chromatin / genetics
  • Chromatin / immunology*
  • Chromatin / metabolism
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / immunology
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Flow Cytometry
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / immunology
  • Forkhead Box Protein O1 / metabolism
  • Gene Expression / immunology
  • Histones / immunology
  • Histones / metabolism
  • Immunoblotting
  • Immunologic Memory / genetics
  • Immunologic Memory / immunology
  • Lysine / immunology
  • Lysine / metabolism
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological
  • Multipotent Stem Cells / immunology
  • Multipotent Stem Cells / metabolism
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / immunology*
  • Polycomb Repressive Complex 2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Chromatin
  • Forkhead Box Protein O1
  • Histones
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • Lysine