De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation

Brian H. Ladle, Kun Po Li, Maggie J. Phillips, Alexandra B. Pucsek, Azeb Haile, Jonathan D. Powell, Elizabeth M. Jaffee, David A. Hildeman, Christopher J. Gamper

Research output: Contribution to journalArticlepeer-review

Abstract

DNMT3a is a de novo DNA methyltransferase expressed robustly after T-cell activation that regulates plasticity of CD4+ T-cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8+ T-cell effector and memory fate decisions. Whereas effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T-cell intrinsic manner compared with wild-type animals. Rather than increasing plasticity of differentiated effector CD8+ T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8+ T cells. These data identify DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions.

Original languageEnglish (US)
Pages (from-to)10631-10636
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016

Keywords

  • Cell differentiation
  • DNA methylation
  • Gene regulation
  • Memory
  • T cells

ASJC Scopus subject areas

  • General

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