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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2014-2022. Prepublished online as a Blood First Edition Paper on October 24, 2006; DOI 10.1182/blood-2006-07-035279. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-07-035279v1 109/5/2014    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 Crellin, N. K Articles by Levings, M. K Search for Related Content PubMed PubMed Citation Articles by Crellin, N. K Articles by Levings, M. K Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 13, 2006 Accepted October 12, 2006 Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells Natasha K Crellin, Rosa V Garcia, and Megan K Levings* University of British Columbia, Canada Vancouver Coastal Health Research Institute, Canada * Corresponding author; email: mlevings{at}interchange.ubc.ca. Suppression by T regulatory cells (Tregs) is a major mechanism by which the immune system controls responses to self and non-harmful foreign proteins. Although there are many different types of Treg cells, the best characterized are those that constitutively express cell-surface IL-2R (CD25). We investigated whether altered TCR-mediated signaling in pure populations of ex vivo human CD4+CD25+ Tregs might underlie their unique phenotype, including hyporesponsiveness to T cell receptor mediated activation and lack of cytokine production. CD4+CD25+ Tregs displayed a consistent defect in phosphorylation of AKT at serine 473, and reduced phosphorylation of the AKT substrates FOXO and S6. Restoration of AKT activity via lenti-viral mediated expression of an inducibly active form of the kinase revealed that reduced activity of this pathway was necessary for the suppressive function of CD4+CD25+ Tregs. These data represent the first demonstration of a causal association between altered signaling and the function of CD4+CD25+ Tregs. Moreover, we have created the first system allowing inducible abrogation of suppression through manipulation of the suppressor cells. This system will be a powerful tool to further study the mechanism(s) of suppression by CD4+CD25+ Tregs. 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] N. R. Locke, S. J. Patterson, M. J. Hamilton, L. M. Sly, G. Krystal, and M. K. Levings SHIP Regulates the Reciprocal Development of T Regulatory and Th17 Cells J. Immunol., July 15, 2009; 183(2): 975 - 983. [Abstract] [Full Text] [PDF] S. M. Henson, O. Franzese, R. Macaulay, V. Libri, R. I. Azevedo, S. Kiani-Alikhan, F. J. Plunkett, J. E. Masters, S. Jackson, S. J. Griffiths, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells Blood, June 25, 2009; 113(26): 6619 - 6628. [Abstract] [Full Text] [PDF] 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] S. Andre, D. F. Tough, S. Lacroix-Desmazes, S. V. Kaveri, and J. Bayry Surveillance of Antigen-Presenting Cells by CD4+CD25+ Regulatory T Cells in Autoimmunity: Immunopathogenesis and Therapeutic Implications Am. J. Pathol., May 1, 2009; 174(5): 1575 - 1587. [Abstract] [Full Text] [PDF] F. Flores-Borja, E. C. Jury, C. Mauri, and M. R. Ehrenstein Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis PNAS, December 9, 2008; 105(49): 19396 - 19401. [Abstract] [Full Text] [PDF] S. Haxhinasto, D. Mathis, and C. Benoist The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells J. Exp. Med., March 17, 2008; 205(3): 565 - 574. [Abstract] [Full Text] [PDF] R. Zeiser, D. B. Leveson-Gower, E. A. Zambricki, N. Kambham, A. Beilhack, J. Loh, J.-Z. Hou, and R. S. Negrin Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells Blood, January 1, 2008; 111(1): 453 - 462. [Abstract] [Full Text] [PDF]

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