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Decreased DNA methyltransferase levels contribute to abnormal gene expression in "senescent" CD4(+)CD28(-) T cells

Ying Liu1, Yingxuan Chen, Bruce Richardson

  • 1Department of Medicine, University of Michigan, USA.

Clinical Immunology (Orlando, Fla.)
|April 28, 2009
PubMed

Insights

Aging and inflammation promote a harmful T cell subset (CD4(+)CD28(-)) that overexpresses specific genes. Decreased DNA methyltransferase enzymes (Dnmt1 and Dnmt3a) cause gene demethylation and overexpression, contributing to disease.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Senescent CD4(+)CD28(-) T cells accumulate with aging and in chronic inflammatory diseases.
  • This T cell subset is linked to cardiovascular events and exhibits pro-inflammatory and cytotoxic properties.
  • Aberrant gene expression, including CD70, perforin, and killer cell immunoglobulin-like receptor (KIR) genes, is characteristic of CD4(+)CD28(-) T cells.

Purpose of the Study:

  • To investigate the mechanisms underlying the overexpression of specific genes in CD4(+)CD28(-) T cells.
  • To determine the role of DNA methylation and DNA methyltransferases in regulating gene expression in this T cell subset.

Main Methods:

  • Analysis of DNA methylation status at CD70, perforin, and KIR2DL4 gene promoters in CD4(+)CD28(-) and CD4(+)CD28(+) T cells.
  • Quantification of DNA methyltransferase 1 (Dnmt1) and Dnmt3a levels in these T cell subsets.
  • siRNA-mediated knockdown of Dnmt1 and Dnmt3a in CD4(+)CD28(+) T cells to assess their functional impact on gene expression and promoter methylation.

Main Results:

  • CD70, perforin, and KIR2DL4 promoters were found to be demethylated in CD4(+)CD28(-) T cells.
  • Levels of DNA methyltransferase 1 (Dnmt1) and Dnmt3a were decreased in the CD4(+)CD28(-) T cell subset.
  • Dnmt1 knockdown in CD4(+)CD28(+) T cells mimicked the demethylation and overexpression of target genes observed in CD4(+)CD28(-) cells.
  • Combined knockdown of Dnmt1 and Dnmt3a resulted in more pronounced demethylation and gene overexpression than Dnmt1 knockdown alone.

Conclusions:

  • Reduced expression of Dnmt1 and Dnmt3a contributes to the demethylation and subsequent overexpression of CD70, perforin, and KIR2DL4 genes in CD4(+)CD28(-) T cells.
  • These epigenetic alterations may underlie the pathogenic functions associated with the CD4(+)CD28(-) T cell subset.
  • Targeting DNA methylation pathways could offer therapeutic strategies for diseases associated with CD4(+)CD28(-) T cells.

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