Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation

Sci Rep. 2020 Apr 16;10(1):6550. doi: 10.1038/s41598-020-63572-w.

Abstract

Human γδ T cells are potent cytotoxic effector cells, produce a variety of cytokines, and can acquire regulatory activity. Induction of FOXP3, the key transcription factor of regulatory T cells (Treg), by TGF-β in human Vγ9 Vδ2 T cells has been previously reported. Vitamin C is an antioxidant and acts as multiplier of DNA hydroxymethylation. Here we have investigated the effect of the more stable phospho-modified Vitamin C (pVC) on TGF-β-induced FOXP3 expression and the resulting regulatory activity of highly purified human Vγ9 Vδ2 T cells. pVC significantly increased the TGF-β-induced FOXP3 expression and stability and also increased the suppressive activity of Vγ9 Vδ2 T cells. Importantly, pVC induced hypomethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene. Genome-wide methylation analysis by Reduced Representation Bisulfite Sequencing additionally revealed differentially methylated regions in several important genes upon pVC treatment of γδ T cells. While Vitamin C also enhances effector functions of Vγ9 Vδ2 T cells in the absence of TGF-β, our results demonstrate that pVC potently increases the suppressive activity and FOXP3 expression in TGF-β-treated Vγ9 Vδ2 T cells by epigenetic modification of the FOXP3 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ascorbic Acid / pharmacology*
  • Cell Proliferation / drug effects
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Demethylation
  • Epigenesis, Genetic / drug effects*
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Phosphorylation / drug effects
  • Protein Stability / drug effects
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / pharmacology

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Receptors, Antigen, T-Cell, gamma-delta
  • Transforming Growth Factor beta
  • Ascorbic Acid