Journal
JOURNAL OF IMMUNOLOGY
Volume 183, Issue 4, Pages 2267-2276Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0802960
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Funding
- National Institutes of Health [T32CA60441]
- Hyundai Scholar Award
- American Cancer Society [RSG0605301LIB]
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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-gamma 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 114 and Ifng loci after activation. Such hypomethylated knockout Th2 cells retain a greater capacity to express IFN-gamma 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 Journal of Immunology, 2009, 183: 2267-2276.
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