期刊
JOURNAL OF IMMUNOLOGY
卷 182, 期 1, 页码 259-273出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.182.1.259
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资金
- National Institute of Health [AI41428, AI62765]
- Juvenile Diabetes Research Foundation [1-2005-16]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI041428, R21AI041428, R01AI062765] Funding Source: NIH RePORTER
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 TGF beta-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 TGF beta-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 Journal of Immunology, 2009, 182: 259-273.
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