title: FoxP3 maintains Treg unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1.
abstract: Regulatory T cells (Tregs) have been shown to play a crucial role in maintaining self-tolerance and suppressing autoimmunity. The forkhead transcription factor, FoxP3, is a key molecule necessary and sufficient for Tregs development and function. However, the molecular mechanisms by which FoxP3 regulates the phenotypic (anergic) and the functional (suppressive) characteristics of Tregs are not well defined. Here we found that the promoter DNA-binding activity of AP-1 transcription factors is selectively inhibited in the naturally occurring CD4+ CD25+ Tregs from mice. The impaired AP-1 DNA binding is not the result of the decreased nuclear translocation of AP-1 family transcription factors, including c-Jun, JunB, and c-Fos. FoxP3 significantly suppresses both the transcriptional activity and promoter DNA-binding of AP-1 by interacting with c-Jun. The N-terminus of FoxP3, but not its C-terminus forkhead domain, specifically interacts with phosphorylated c-Jun and alters c-Jun subnuclear distribution. This N-terminus of FoxP3 with nuclear localization signals (FoxP3N/NLS) is able to suppress AP-1 transcriptional activity. Ectopic expression of FoxP3N/NLS sufficiently induces the unresponsiveness of mouse primary CD4+ CD25- T cells, whereas the full-length FoxP3 is required for the suppressive functions of Tregs. These findings uncover one of the mechanisms underlying how FoxP3 maintains the unresponsiveness of Tregs.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Missouri-Columbia School of Medicine 65212, USA.
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017635:Clonal Anergy / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019913:Nuclear Localization Signals / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000502:physiology; D017634:Self Tolerance / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019913:Nuclear Localization Signals; D018808:Transcription Factor AP-1; D014157:Transcription Factors