title: Epigenetic control of the foxp3 locus in regulatory T cells.
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-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.
authors.affiliation: Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freyer
authors.forename: Christiane
authors.initials: C
authors.lastname: Siewert
authors.forename: Udo
authors.initials: U
authors.lastname: Baron
authors.forename: Sven
authors.initials: S
authors.lastname: Olek
authors.forename: Julia
authors.initials: J
authors.lastname: Polansky
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schlawe
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein-Hessling
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
mesh_terms: D000818:Animals; D001483:Base Sequence; D002469:Cell Separation; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D053645:Interleukin-2 Receptor alpha Subunit; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit