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

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

Research output: Contribution to journalArticle

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

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Keywords

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

ASJC Scopus subject areas

  • General

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