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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3599-3606. Prepublished online as a Blood First Edition Paper on January 25, 2008; DOI 10.1182/blood-2007-09-115014. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-09-115014v1 111/7/3599    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lee, S.-M. Articles by Fang, D. Search for Related Content PubMed PubMed Citation Articles by Lee, S.-M. Articles by Fang, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 26, 2007 Accepted January 18, 2008 FoxP3 maintains Tregs unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1 Sang-Myeong Lee, Beixue Gao, and Deyu Fang* Department of Otolaryngology-Head and Neck surgery, University of Missouri-Columbia School of Medicine, Columbia, MO, United States Department of Molecular Microbiology and Immunology, University of Missouri-Columbia School of Medicine, Columbia, MO, United States * Corresponding author; email: fangd{at}missouri.edu. 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 due to the decreased nuclear translocation of AP-1 family transcription factors including c-Jun, JunB and c-Fos. FoxP3 sufficiently 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 sufficient to suppress AP-1 transcriptional activity. Ecotopic expression of FoxP3N/NLS sufficiently induced the unresponsiveness of mouse primary CD4+CD25- T cells, while 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Pozo, P. Anderson, and E. Gonzalez-Rey Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide J. Immunol., October 1, 2009; 183(7): 4346 - 4359. [Abstract] [Full Text] [PDF] A. D. Wells New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting J. Immunol., June 15, 2009; 182(12): 7331 - 7341. [Abstract] [Full Text] [PDF] L.-F. Lu and A. Rudensky Molecular orchestration of differentiation and function of regulatory T cells Genes & Dev., June 1, 2009; 23(11): 1270 - 1282. [Abstract] [Full Text] [PDF] E. F. de Zoeten, I. Lee, L. Wang, C. Chen, G. Ge, A. D. Wells, W. W. Hancock, and E. Ozkaynak Foxp3 Processing by Proprotein Convertases and Control of Regulatory T Cell Function J. Biol. Chem., February 27, 2009; 284(9): 5709 - 5716. [Abstract] [Full Text] [PDF]

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