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Blood, 1 January 2008, Vol. 111, No. 1, pp. 453-462. Prepublished online as a Blood First Edition Paper on October 29, 2007; DOI 10.1182/blood-2007-06-094482. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-094482v1 111/1/453    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 Zeiser, R. Articles by Negrin, R. S. Search for Related Content PubMed PubMed Citation Articles by Zeiser, R. Articles by Negrin, R. S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 7, 2007 Accepted October 26, 2007 Differential impact of mTOR inhibition on CD4+CD25+Foxp3+ regulatory T cells as compared to conventional CD4+ T cells Robert Zeiser, Dennis B. Leveson-Gower, Elizabeth A. Zambricki, Neeraja Kambham, Andreas Beilhack, John Loh, Jing-Zhou Hou, and Robert S. Negrin* Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, United States Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States * Corresponding author; email: negrs{at}stanford.edu. Based on their ability to control T cell homeostasis, Foxp3+CD4+CD25+ regulatory T cells (Treg) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGvHD). When combining Treg with the immunosuppressant rapamycin (RAPA) we observed reduced alloreactive conventional T cell (Tconv) expansion and aGvHD lethality as compared to each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Treg with conserved high FoxP3 expression. In contrast to Tconv, activation of Treg with allo-antigen and IL-2 preferentially led to STAT5 phosphorylation and not PI3K/Akt/mTOR pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Treg but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Treg to mTOR inhibition by RAPA. Differential impact of RAPA due to reduced usage of the mTOR pathway in Treg as compared to conventional T cells explains the synergistic effect of RAPA and Treg in aGvHD protection which has important implications for clinical trials utilizing Treg. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. Bommhardt Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation J. Immunol., November 15, 2009; 183(10): 6124 - 6134. [Abstract] [Full Text] [PDF] G. Socie and B. R. Blazar Acute graft-versus-host disease: from the bench to the bedside Blood, November 12, 2009; 114(20): 4327 - 4336. [Abstract] [Full Text] [PDF] N. Beyersdorf, X. Ding, T. Hunig, and T. 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