Epigenetic control of the foxp3 locus in regulatory T cells.
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.
Floess
Stefan
S
Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Berlin, Germany.
Freyer
Jennifer
J
Siewert
Christiane
C
Baron
Udo
U
Olek
Sven
S
Polansky
Julia
J
Schlawe
Kerstin
K
Chang
Hyun-Dong
HD
Bopp
Tobias
T
Schmitt
Edgar
E
Klein-Hessling
Stefan
S
Serfling
Edgar
E
Hamann
Alf
A
Huehn
Jochen
J
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
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit