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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2940-2947. Prepublished online as a Blood First Edition Paper on July 12, 2007; DOI 10.1182/blood-2007-04-086751. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-086751v1 110/8/2940    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 Ji, H. Articles by Rommel, C. Search for Related Content PubMed PubMed Citation Articles by Ji, H. Articles by Rommel, C. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Inactivation of PI3K and PI3K distorts T-cell development and causes multiple organ inflammation Hong Ji1, Felix Rintelen1, Caroline Waltzinger1, Dominique Bertschy Meier1, Antonio Bilancio2, Wayne Pearce2, Emilio Hirsch3, Matthias P. Wymann4, Thomas Rückle1, Montserrat Camps1, Bart Vanhaesebroeck2, Klaus Okkenhaug5, and Christian Rommel1 1 Merck Serono S. A., Geneva Research Center, Geneva, Switzerland; 2 Ludwig Institute for Cancer Research, London, United Kingdom; 3 Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy; 4 Institute of Biochemistry & Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland; and 5 Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, United Kingdom Mice lacking both the p110 and p110 isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110–/–/p110D910A/D910A (p110KOD910A) mice where the p110 isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110 deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses. Using small-molecule selective inhibitors, we demonstrated that in mature T cells, p110, but not p110, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Doukas, L. Eide, K. Stebbins, A. Racanelli-Layton, L. Dellamary, M. Martin, E. Dneprovskaia, G. Noronha, R. Soll, W. Wrasidlo, et al. Aerosolized Phosphoinositide 3-Kinase {gamma}/{delta} Inhibitor TG100-115 [3-[2,4-Diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease J. Pharmacol. Exp. Ther., March 1, 2009; 328(3): 758 - 765. [Abstract] [Full Text] [PDF] S. Konrad, S. R. Ali, K. Wiege, S. N. Syed, L. Engling, R. P. Piekorz, E. Hirsch, B. Nurnberg, R. E. Schmidt, and J. E. Gessner Phosphoinositide 3-Kinases {gamma} and {delta}, Linkers of Coordinate C5a Receptor-Fc{gamma} Receptor Activation and Immune Complex-induced Inflammation J. Biol. Chem., November 28, 2008; 283(48): 33296 - 33303. [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. Biol., September 1, 2008; 84(3): 814 - 823. [Abstract] [Full Text] [PDF] A. L. Martin, M. D. Schwartz, S. C. Jameson, and Y. Shimizu Selective Regulation of CD8 Effector T Cell Migration by the p110{gamma} Isoform of Phosphatidylinositol 3-Kinase J. Immunol., February 15, 2008; 180(4): 2081 - 2088. [Abstract] [Full Text] [PDF] S. J. Harris, R. V. Parry, J. Westwick, and S. G. Ward Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes J. Biol. Chem., February 1, 2008; 283(5): 2465 - 2469. [Abstract] [Full Text] [PDF] F. Garcon, D. T. Patton, J. L. Emery, E. Hirsch, R. Rottapel, T. Sasaki, and K. Okkenhaug CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer Blood, February 1, 2008; 111(3): 1464 - 1471. [Abstract] [Full Text] [PDF]

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