DNA methylation is a nonredundant repressor of the Th2 effector program.
The extent to which DNA methylation contributes to proper regulation of murine T cell effector function is unclear. In this study, we show that in the absence of the maintenance DNA methyltransferase Dnmt1, silencing of IL-4, IL-5, IL-13, and IL-10 in CD8 T cells was abolished, and expression of these Th2 cytokines increased as much as 1000-fold compared with that of control CD8 T cells. Th2 cytokine expression also increased in Dnmt1(-/-) CD4 T cells, but the increase ( approximately 20-40-fold for IL-4 and IL-10, </=5-fold for IL-5 and IL-13) was less than for CD8 T cells. As a result, both Dnmt1(-/-) CD4 and CD8 T cells expressed high and comparable amounts of Th2 cytokines. Loss of Dnmt1 had more subtle effects on IL-2 (</=5-fold increase) and IFN-gamma ( approximately 5-10-fold increase) expression and did not affect the normal bias for greater IL-2 expression by CD4 T cells and greater IFN-gamma expression by CD8 T cells, nor the exclusive expression of perforin and granzyme B by the CD8 T cells. These results indicate that Dnmt1 and DNA methylation are necessary to prevent cell autonomous Th2 cytokine expression in CD8 T cells but are not essential for maintaining proper T cell subset-specific expression of Th1 or CTL effectors. We also found that the expression of Th2 cytokines by Dnmt1(-/-) T cells was appropriately up-regulated in Th2 conditions and down-regulated in Th1 conditions, indicating that transcription factors and DNA methylation are complementary and nonredundant mechanisms by which the Th2 effector program is regulated.
Makar
Karen W
KW
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Wilson
Christopher B
CB
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D012097:Repressor Proteins; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse