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

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: simon.gray@yale.edu.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA; Interdepartmental Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: susan.kaech@yale.edu.

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

PMID:
28410989
PMCID:
PMC5457165
DOI:
10.1016/j.immuni.2017.03.012
[Indexed for MEDLINE]
Free PMC Article

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