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International Immunology Advance Access first published online on June 20, 2008
This version published online on July 9, 2008
International Immunology, doi:10.1093/intimm/dxn062
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Meital Nagar1,2, Helly Vernitsky1, Yoram Cohen1, Dan Dominissini1, Yackov Berkun3, Gideon Rechavi1,3, Ninette Amariglio1,4 and Itamar Goldstein1,5

1 Sheba Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv University—Sackler Faculty of Medicine, Israel
2 The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Israel
3 Division of Pediatrics
4 Institute of Hematology
5 Rheumatology Unit, The Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv University—Sackler Faculty of Medicine, Israel

Correspondence to: Correspondence to: I. Goldstein; E-mail: itamar.goldstein{at}sheba.health.gov.il

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.

Keywords: gene regulation, human, regulatory T cells, immunological tolerance, transcription factor, forkhead box P3

Transmitting editor: K. Yamamoto

Received 17 January 2008, accepted 22 May 2008.


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