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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1464-1471. Prepublished online as a Blood First Edition Paper on November 15, 2007; DOI 10.1182/blood-2007-08-108050. This Article Full Text (PDF) Supplemental Figures and Videos All Versions of this Article: blood-2007-08-108050v1 111/3/1464    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 Garcon, F. Articles by Okkenhaug, K. Search for Related Content PubMed PubMed Citation Articles by Garcon, F. Articles by Okkenhaug, K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 20, 2007 Accepted November 12, 2007 CD28 provides T cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer Fabien Garcon, Daniel T Patton, Juliet L Emery, Emilio Hirsch, Robert Rottapel, Takehiko Sasaki, and Klaus Okkenhaug* Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy Division of Stem Cells and Developmental Biology, Princess Margaret Hospital/Ontario Cancer Institute, Toronto, Canada Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan * Corresponding author; email: klaus.okkenhaug{at}bbsrc.ac.uk. Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Here we show, using a quantitative imaging-based assay, that the PI3K activity at the T cell - APC contact area is dependent on the p110 but not the p110, isoform of PI3K. CD28 enhanced PIP3 production at the T cell synapse independently of its YMNM PI3K-recruitment motif which instead was required for efficient PKC recruitment. CD28 could partially compensate for the lack of p110 activity during T cell activation which indicates that CD28 and p110 act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110 double deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutical targeting of p110 activity and CD28 costimulation has potent therapeutic potential. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. J. Salmond, J. Emery, K. Okkenhaug, and R. Zamoyska MAPK, Phosphatidylinositol 3-Kinase, and Mammalian Target of Rapamycin Pathways Converge at the Level of Ribosomal Protein S6 Phosphorylation to Control Metabolic Signaling in CD8 T Cells J. Immunol., December 1, 2009; 183(11): 7388 - 7397. [Abstract] [Full Text] [PDF] C. Waugh, L. Sinclair, D. Finlay, J. R. Bayascas, and D. Cantrell Phosphoinositide (3,4,5)-Triphosphate Binding to Phosphoinositide-Dependent Kinase 1 Regulates a Protein Kinase B/Akt Signaling Threshold That Dictates T-Cell Migration, Not Proliferation Mol. Cell. Biol., November 1, 2009; 29(21): 5952 - 5962. [Abstract] [Full Text] [PDF] C.-H. Hsieh, J.-T. Hsu, Y.-C. Hsieh, M. Frink, R. Raju, W. J. 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Barber, and A. C. Carrera p85{beta} phosphoinositide 3-kinase regulates CD28 coreceptor function Blood, April 2, 2009; 113(14): 3198 - 3208. [Abstract] [Full Text] [PDF] E. Zebedin, O. Simma, C. Schuster, E. M. Putz, S. Fajmann, W. Warsch, E. Eckelhart, D. Stoiber, E. Weisz, J. A. Schmid, et al. Leukemic challenge unmasks a requirement for PI3K{delta} in NK cell-mediated tumor surveillance Blood, December 1, 2008; 112(12): 4655 - 4664. [Abstract] [Full Text] [PDF] T. Letschka, V. Kollmann, C. Pfeifhofer-Obermair, C. Lutz-Nicoladoni, G. J. Obermair, F. Fresser, M. Leitges, N. Hermann-Kleiter, S. Kaminski, and G. Baier PKC-{theta} selectively controls the adhesion-stimulating molecule Rap1 Blood, December 1, 2008; 112(12): 4617 - 4627. [Abstract] [Full Text] [PDF] M. S. Thomas, J. S. Mitchell, C. C. DeNucci, A. L. Martin, and Y. Shimizu The p110{gamma} isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites J. Leukoc. 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