Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation.
Regulatory T cells (T(reg)) express Foxp3, a forkhead family member that is necessary and sufficient for T(reg) lineage choice and function. Ectopic expression of Foxp3 in non-T(reg) leads to repression of the interleukin 2 (IL-2) and interferon gamma (IFNgamma) genes, gain of suppressor function, and induction of genes such as CD25, GITR, and CTLA-4, but the mode by which Foxp3 enforces this program is unclear. Using chromatin immunoprecipitation, we have demonstrated that Foxp3 binds to the endogenous IL-2 and IFNgamma loci in T cells, but only after T cell receptor stimulation. This activation-induced Foxp3 binding was abrogated by cyclosporin A, suggesting a role for the phosphatase calcineurin in Foxp3 function. We have also shown that binding of Foxp3 to the IL-2 and IFNgamma genes induces active deacetylation of histone H3, a process that inhibits chromatin remodeling and opposes gene transcription. Conversely, binding of Foxp3 to the GITR, CD25, and CTLA-4 genes results in increased histone acetylation. These data indicate that Foxp3 may regulate transcription through direct chromatin remodeling and show that Foxp3 function is influenced by signals from the TCR.
Chen
Chunxia
C
Joseph Stokes, Jr. Research Institute, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Rowell
Emily A
EA
Thomas
Rajan M
RM
Hancock
Wayne W
WW
Wells
Andrew D
AD
D000107:Acetylation; D000818:Animals; D016572:Cyclosporine / Q000737:chemistry; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000502:physiology*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D016572:Cyclosporine