Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation.
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 TGFbeta-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 TGFbeta-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.
Lal
Girdhari
G
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zhang
Nan
N
van der Touw
William
W
Ding
Yaozhong
Y
Ju
Wenjun
W
Bottinger
Erwin P
EP
Reid
St Patrick
SP
Levy
David E
DE
Bromberg
Jonathan S
JS
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D019175:DNA Methylation / Q000187:drug effects / Q000276:immunology*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000077209:Decitabine; D001374:Azacitidine