Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells

Meital Nagar, Helly Vernitsky, Yoram Cohen, Dan Dominissini, Yackov Berkun, Gideon Rechavi, Ninette Amariglio, Itamar Goldstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4+CD25- T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells - hence not Treg restricted - is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4+CD25- T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4+ T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25- T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4+CD25+ T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor β. In contrast to natural Treg, such induced CD4+ FOXP3+ T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells.

Original languageEnglish
Pages (from-to)1041-1055
Number of pages15
JournalInternational Immunology
Issue number8
StatePublished - Aug 2008


  • Forkhead box P3
  • Gene regulation
  • Human
  • Immunological tolerance
  • Regulatory T cells
  • Transcription factor


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