Differential Patterns of Methylation of the IFN-#gamma# Promoter at CpG and Non-CpG Sites Underlie Differences in IFN-#gamma# Gene Expression Betweeen Human Neonatal and Adult CD45RO~- T Cells~1

摘要

IFN-#gamma# is potent pleiotropic Th1 cytokine,t eh production of which is tightly regulated during fetal development, negative control of fetaleonatal 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 CD~+ 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-#gamma#R #gamma#-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.