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Epigenetic Control of the foxp3 Locus in Regulatory T Cells
Open accessAbstract
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-beta in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-beta-induced Foxp3(+) Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-beta. 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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Metadata
- Authors
- Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.-D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., & Huehn, J.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2007-01-30
- Volume
- 5
- Issue
- 2
- Pages
- e38
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W1983019708
- Cited by
- 1,270
- References
- 3
- FWCI
- 24.79
- Type
- journal article
- Language
- en
- Open access
- gold
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