DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells

Eur J Immunol. 2007 Sep;37(9):2378-89. doi: 10.1002/eji.200737594.


The transcription factor FOXP3 is critical for development and function of regulatory T cells (Treg). Their number and functioning appears to be crucial in the prevention of autoimmunity and allergy, but also to be a negative prognostic marker for various solid tumors. Although expression of the transcription factor FOXP3 currently constitutes the best-known marker for Treg, in humans, transient expression is also observed in activated non-Treg. Extending our recent findings for the murine foxp3 locus, we observed epigenetic modification of several regions in the human FOXP3 locus exclusively occurring in Treg. Importantly, activated conventional CD4(+) T cells and TGF-beta-treated cells displayed no FOXP3 DNA demethylation despite expression of FOXP3, whereas subsets of Treg stable even upon extended in vitro expansion remained demethylated. To investigate whether a whole set of genes might be epigenetically imprinted in the Treg lineage, we conducted a genome-wide differential methylation hybridization analysis. Several genes were found displaying differential methylation between Treg and conventional T cells, but none beside FOXP3 turned out to be entirely specific to Treg when tested on a broad panel of cells and tissues. We conclude that FOXP3 DNA demethylation constitutes the most reliable criterion for natural Treg available at present.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • DNA Methylation
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling
  • Genetic Markers
  • Humans
  • Immunity, Innate / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation / immunology*
  • Male
  • Sensitivity and Specificity
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / pharmacology


  • CAMTA1 protein, human
  • Calcium-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Genetic Markers
  • Interleukin-2 Receptor alpha Subunit
  • Trans-Activators
  • Transforming Growth Factor beta