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

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. While 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 to 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. This data identifies DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions. Examination of global genomic DNA methylation by MBD-seq in naïve CD8 T cells and CD8 T cells 8 days post Vaccinia-Ova infection, comparing OT1 TCR-Tg CD8 T cells isolated from WT and T cell conditional DNMT3a KO mice.

ORGANISM(S): Mus musculus

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

PROVIDER: E-GEOD-85823 | ArrayExpress | 2016-09-12

SECONDARY ACCESSION(S): GSE85823SRP082394PRJNA339495

REPOSITORIES: GEO, ArrayExpress, ENA

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