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 Foxp3CD25CD4 Tregs, but not in nave CD25CD4 T cells. Partial DNA demethylation is already found within developing Foxp3 thymocytes; however, Tregs induced by TGF- in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-induced Foxp3 Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-. 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.
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