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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 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 Citation Map 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. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Notch1 and TGFβ1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells Jeremy B. Samon1,2, Ameya Champhekar2,3, Lisa M. Minter2, Janice C. Telfer2, Lucio Miele4, Abdul Fauq5, Pritam Das5, Todd E. Golde5, and Barbara A. Osborne2,3 1 Program in Animal Biotechnology and Biomedical Science, 2 Department of Veterinary and Animal Sciences, and 3 Molecular and Cellular Biology Program, University of Massachusetts Amherst; 4 Department of Pathology, Pharmacology and Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University, Chicago, IL; and 5 Department of Neuroscience, Mayo Clinic, Jacksonville, FL Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Tregs), 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 (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using -secretase inhibitor (GSI) treatment blocks (1) TGFβ1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, 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 development of symptoms consistent with autoimmune hepatitis, a disease previously found to result from dysregulation of TGFβ signaling and regulatory T cells. Together, these findings indicate that the Notch and TGFβ 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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