De Novo DNA Methylation by DNA Methyltransferase 3A Controls Early Effector CD8+ T-Cell Fate Decisions Following Activation
De novo DNA methylation by DNA methyltransferase + 3a controls early effector CD8 T-cell fate decisions following activation Brian H. Ladlea,1,2, Kun-Po Lib,c,1, Maggie J. Phillipsa, Alexandra B. Pucseka, Azeb Hailea, Jonathan D. Powella, Elizabeth M. Jaffeea, David A. Hildemanb,c,1,2, and Christopher J. Gampera,1 aDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; bImmunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220; and cDivision of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229 Edited by Susan M. Kaech, Yale University School of Medicine, New Haven, CT, and accepted by Editorial Board Member Philippa Marrack July 18, 2016 (received for review December 11, 2015) DNMT3a is a de novo DNA methyltransferase expressed robustly dominant DNA methyltransferase active in T cells (18, 19). In + + after T-cell activation that regulates plasticity of CD4 T-cell cyto- CD4 T cells, DNMT3a plays a key role in lineage stability and kine expression. Here we show that DNMT3a is critical for direct- restricting plasticity. DNMT3a mediates CpG DNA methylation ing early CD8+ T-cell effector and memory fate decisions. Whereas and silencing of the Ifng promoter during Th2 differentiation effector function of DNMT3a knockout T cells is normal, they de- (20) and the Il13 promoter in an asthma model (19). In both of + velop more memory precursor and fewer terminal effector cells in these models, DNMT3a functions in CD4 T cells to control the a T-cell intrinsic manner compared with wild-type animals.
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