Abstract
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 naïve CD25−CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-β in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-β–induced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-β. 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.
Highlights
Regulatory T cells (Tregs), which have been shown to play a pivotal role in the maintenance of self-tolerance within the immune system, were described originally as CD4þ T cells constitutively expressing CD25 [1]
Regulatory T cells play a pivotal role in the maintenance of selftolerance within the immune system by preventing autoimmunity or excessive activation of the T cells that respond to pathogens
Our study provides evidence for a critical role of epigenetic modifications in the locus coding for the forkhead transcription factor Foxp3, which acts as a master switch controlling regulatory T cell development and function: An evolutionarily conserved region within the non-coding part of the gene contains CpG motifs, which are completely demethylated in regulatory T cells, but methylated in naıve and effector T cells, whereas we observed an inverse occurrence of acetylated histones, another epigenetic chromatin modification
Summary
Regulatory T cells (Tregs), which have been shown to play a pivotal role in the maintenance of self-tolerance within the immune system, were described originally as CD4þ T cells constitutively expressing CD25 [1]. Mutation or deletion of the gene encoding Foxp causes severe autoimmune disease in mice and humans, due to a failure to generate CD25þCD4þ Tregs [3,4], whereas ectopic expression of Foxp in conventional T cells confers suppressive activity [4,5]. These findings provided compelling evidence that Foxp acts as a master switch controlling the development and function of Tregs; the molecular mechanisms leading to its induction remain largely unknown. To what extent these induced populations of Tregs acquire a stable phenotype corresponding to that of natural, thymus-derived Tregs is, unclear
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