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* Department of Gene and Cell Medicine,
Department of Surgery,
Recanati/Miller Transplantation Institute,
Immunology Center, and
¶ Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029; and
|| Department of Pathology and Microbiology, New York University School of Medicine, New York, NY 10016
Foxp3, a winged-helix family transcription factor, serves as the master switch for CD4+ regulatory T cells (Treg). We identified a unique and evolutionarily conserved CpG-rich island of the Foxp3 nonintronic upstream enhancer and discovered that a specific site within it was unmethylated in natural Treg (nTreg) but heavily methylated in naive CD4+ T cells, activated CD4+ T cells, and peripheral TGFβ-induced Treg in which it was bound by DNMT1, DNMT3b, MeCP2, and MBD2. Demethylation of this CpG site using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza) induced acetylation of histone 3, interaction with TIEG1 and Sp1, and resulted in strong and stable induction of Foxp3. Conversely, IL-6 resulted in methylation of this site and repression of Foxp3 expression. Aza plus TGFβ-induced Treg resembled nTreg, expressing similar receptors, cytokines, and stable suppressive activity. Strong Foxp3 expression and suppressor activity could be induced in a variety of T cells, including human CD4+CD25– T cells. Epigenetic regulation of Foxp3 can be predictably controlled with DNMT inhibitors to generate functional, stable, and specific Treg.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Health Grants AI41428 and AI62765 and Juvenile Diabetes Research Foundation Grant 1-2005-16 (all to J.S.B.).
2 Address correspondence and reprint requests to Dr. Jonathan S. Bromberg, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1104, New York, NY 10029-6574. E-mail address: Jon.Bromberg{at}mountsinai.org
3 Abbreviations used in this paper: Treg, regulatory T cell; AcH3, acetylated histone 3; AID, activation-induced cytidine deaminase; ATF, activating transcription factor; Aza, 5-aza-2'-deoxycytidine; ChIP, chromatin immunoprecipitation; DNMT, DNA methyltransferase; EGR1, early growth response 1; HDAC, histone deacetylase; nTreg, natural Treg; qRT-PCR, quantitative RT-PCR; TIEG1, TGFβ-inducible early gene-1.
4 The online version of this article contains supplemental material.
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