Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation.
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 Il4 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.
Gamper
Christopher J
CJ
Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
Agoston
Agoston T
AT
Nelson
William G
WG
Powell
Jonathan D
JD
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D000090205:DNA Methyltransferase 3A; D005819:Genetic Markers / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C000715535:Dnmt3a protein, mouse; D005819:Genetic Markers; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A