title: 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. 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.
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231; bladle@jhmi.edu David.Hildeman@cchmc.org.
authors: Brian H
authors: BH
authors: Ladle
authors: Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220; Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors: Kun-Po
authors: KP
authors: Li
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Maggie J
authors: MJ
authors: Phillips
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Alexandra B
authors: AB
authors: Pucsek
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Azeb
authors: A
authors: Haile
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Jonathan D
authors: JD
authors: Powell
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Elizabeth M
authors: EM
authors: Jaffee
authors: Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220; Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229 bladle@jhmi.edu David.Hildeman@cchmc.org.
authors: David A
authors: DA
authors: Hildeman
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
authors: Christopher J
authors: CJ
authors: Gamper
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D000090205:DNA Methyltransferase 3A; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D007156:Immunologic Memory / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011401:Promoter Regions, Genetic; D051822:T Cell Transcription Factor 1 / Q000235:genetics*
chemical_list: C000715535:Dnmt3a protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051822:T Cell Transcription Factor 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; T cells; cell differentiation; gene regulation; memory