Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation

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Abstract

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-γ 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-γ 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.

Original languageEnglish (US)
Pages (from-to)2267-2276
Number of pages10
JournalJournal of Immunology
Volume183
Issue number4
DOIs
StatePublished - Aug 15 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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