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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1813-1821. Prepublished online as a Blood First Edition Paper on June 11, 2008; DOI 10.1182/blood-2008-03-144980. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-144980v1 112/5/1813    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 Samon, J. B. Articles by Osborne, B. A Search for Related Content PubMed PubMed Citation Articles by Samon, J. B. Articles by Osborne, B. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 13, 2008 Accepted May 23, 2008 Notch1 and TGF1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells Jeremy B. Samon, Ameya Champhekar, Lisa M Minter, Janice C. Telfer, Lucio Miele, Abdul Fauq, Pritam Das, Todd E Golde, and Barbara A Osborne* Program in Animal Biotechnology, University of Massachusetts, Amherst, MA, United States Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA, United States Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United States Department of Pathology, Pharmacology and Breast Cancer Program, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Chicago, IL, United States Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States * Corresponding author; email: osborne{at}vasci.umass.edu. Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Treg), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGF1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling with -secretase inhibitor (GSI) treatment blocks i) TGF1-induced Foxp3 expression, ii) the upregulation of Foxp3-target genes, and iii) the ability to suppress naive T cell proliferation. Additionally, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and the development of symptoms of autoimmune hepatitis, a disease previously found to result from dysregulation of TGF signaling and regulatory T cells. Together, these findings indicate that the Notch and TGF signaling pathways cooperatively regulate Foxp3 expression and regulatory T cell maintenance both in vitro and in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. F. Campese, P. Grazioli, S. Colantoni, E. Anastasi, M. Mecarozzi, S. Checquolo, G. De Luca, D. Bellavia, L. Frati, A. Gulino, et al. Notch3 and pT{alpha}/pre-TCR sustain the in vivo function of naturally occurring regulatory T cells Int. Immunol., June 1, 2009; 21(6): 727 - 743. [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]

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