Differential patterns of methylation of the IFN-γ promoter at CpG and Non-CpG sites underlie differences in IFN-γ gene expression between human neonatal and adult CD45RO- T cells

被引:256
作者
White, GP
Watt, PM
Holt, BJ
Holt, PG
机构
[1] Univ Western Australia, Ctr Child Hlth Res, Perth, WA 6009, Australia
[2] TVW Telethon Inst Child Hlth Res, Perth, WA, Australia
关键词
D O I
10.4049/jimmunol.168.6.2820
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IFN-gamma is a potent pleiotropic Th1 cytokine, the production of which is tightly regulated during fetal development. Negative control of fetal/neonatal IFN-gamma production is generally attributed to the Th1-antagonistic effect of mediators produced by the placenta, but evidence exists of additional and more direct transcriptional regulation. We report that neonatal (cord blood) CD3(+)/ CD45RO(-) T cells, in particular the CD4(+)/CD45RO(-) subset, are hypermethylated at CpG and non-CpG (CpA and CpT) sites within and adjacent to the IFN-gamma promoter. In contrast, CpG methylation patterns in cord blood IFN-gamma-producing CD8(+)/ CD45RO- T cells and CD56(+)/CD16(+)/CD3(-) NK cells did not differ significantly from those in their adult counterparts. Consistent with this finding, IFN-gamma production by stimulated naive cord blood CD4(+) T cells is reduced 5- to 10-fold relative to adult CD4(+) T cells, whereas production levels in neonatal and adult CD8(+) T cells are of a similar order. Evidence of significant CpA and CpT methylation was not discovered in promoter sequence from other cytokines (IL-4, TNF-alpha, or IFN-gammaR alpha-chain). We additionally demonstrate that overexpression of DNA methyltransferase 3a in embryonic kidney carcinoma cells Is accompanied by CpA methylation of the IFN-gamma promoter.
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页码:2820 / 2827
页数:8
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