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Identification of DNA Methyltransferase 3a as a T Cell Receptor-Induced Regulator of Th1 and Th2 Differentiation¹

Christopher J. Gamper^*, Agoston T. Agoston, William G. Nelson^* and Jonathan D. Powell^2,*

^* Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD 21231; and Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115

Ag-specific T cell cytokine expression is dictated by the context in which TCR engagement occurs. Recently it has become clear that epigenetic changes play a role in this process. DNA methyltransferase 3a (DNMT3a) is a de novo methyltransferase important to the epigenetic control of cell fate. We have determined that DNMT3a expression is increased following TCR engagement and that costimulation mitigates DNMT3a protein expression. T cells lacking DNMT3a simultaneously express IFN- and IL-4 after expansion under nonbiasing conditions. While global methylation of DNA from wild-type and knockout T cells is similar, DNMT3a-null T cells demonstrate selective hypomethylation of both the Il4 and Ifng loci after activation. Such hypomethylated knockout Th2 cells retain a greater capacity to express IFN- protein when they are subsequently exposed to Th1-biasing conditions. Based on these findings we propose that DNMT3a is a key participant in regulating T cell polarization at the molecular level by promoting stable selection of a context-specific cell fate through methylation of selective targets in T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grant T32CA60441 (to C.G.), a Hyundai Scholar Award (to C.G.), and American Cancer Society Grant RSG0605301LIB (to J.P.).

² Address correspondence and reprint requests to Dr. Jonathan D. Powell, Department of Oncology, Johns Hopkins University, School of Medicine, 1650 Orleans Street, Cancer Research Building 1, Room 443, Baltimore, MD 21231. E-mail address: poweljo{at}jhmi.edu

³ Abbreviations used in this paper: DNMT, DNA methyltransferase; 5C.C7, B10.A/AiTac-[Tg]TCRCyt5CC7-I-[KO]Rag2 mouse; ICS, intracellular cytokine staining; KO, knockout; WT, wild type.