IFN-γ is a potent pleiotropic Th1 cytokine, the production of which is tightly regulated during fetal development. Negative control of fetal/neonatal IFN-γ 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-γ promoter. In contrast, CpG methylation patterns in cord blood IFN-γ-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-γ 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-α, or IFN-γR α-chain). We additionally demonstrate that overexpression of DNA methyltransferase 3a in embryonic kidney carcinoma cells is accompanied by CpA methylation of the IFN-γ promoter.
White, G. P., Watt, P. M., Holt, B. J., & Holt, P. G. (2002). 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 . The Journal of Immunology, 168(6), 2820–2827. https://doi.org/10.4049/jimmunol.168.6.2820