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Promoter at CpG and Non-CpG Sites Underlie Differences in IFN- Gene Expression Between Human Neonatal and Adult CD45RO- T Cells1
TVW Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia
IFN-
is a potent pleiotropic Th1 cytokine, the production of
which is tightly regulated during fetal development. Negative control
of fetal/neonatal IFN- 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-
promoter. In contrast, CpG methylation patterns in cord blood
IFN--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- 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-
, or IFN-R
-chain). We additionally demonstrate that overexpression of
DNA methyltransferase 3a in embryonic kidney carcinoma cells is
accompanied by CpA methylation of the IFN-
promoter.
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