%0 Journal Article
%T Epigenetic Control of the foxp3 Locus in Regulatory T Cells
%A Stefan Floess
%A Jennifer Freyer
%A Christiane Siewert
%A Udo Baron
%A Sven Olek
%A Julia Polansky
%A Kerstin Schlawe
%A Hyun-Dong Chang
%A Tobias Bopp
%A Edgar Schmitt
%A Stefan Klein-Hessling
%A Edgar Serfling
%A Alf Hamann
%A Jochen Huehn
%J PLOS Biology
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pbio.0050038
%X Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4+ regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3+CD25+CD4+ Tregs, but not in na£¿ve CD25£¿CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-¦Â in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-¦Â¨Cinduced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-¦Â. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.
%U http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0050038