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

J Immunol. 2002 Mar 15;168(6):2820-7. doi: 10.4049/jimmunol.168.6.2820.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine
  • Adenine / metabolism
  • Adult
  • CD3 Complex / biosynthesis
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Calcium-Binding Proteins
  • Cloning, Molecular
  • CpG Islands / drug effects
  • CpG Islands / immunology*
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA Methylation*
  • DNA Methyltransferase 3A
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dinucleotide Repeats / immunology
  • Fetal Blood / immunology
  • Fetal Blood / metabolism*
  • Gene Expression Regulation / immunology*
  • Humans
  • Infant, Newborn
  • Interferon-gamma / genetics*
  • Interferon-gamma / metabolism*
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Leukocyte Common Antigens / biosynthesis*
  • Microfilament Proteins
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / immunology*
  • Sequence Analysis, DNA
  • Sulfites / pharmacology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • Thymine / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • AIF1 protein, human
  • CD3 Complex
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • DNMT3A protein, human
  • Microfilament Proteins
  • Sulfites
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • 5-Methylcytosine
  • Interferon-gamma
  • Cytosine
  • DNA Methyltransferase 3A
  • Leukocyte Common Antigens
  • Adenine
  • Thymine