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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2415-2422.
Prepublished online as a Blood First Edition Paper on November 22, 2005; DOI 10.1182/blood-2005-08-3300.
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Submitted August 15, 2005
Accepted October 30, 2005
The essential role of PI3K and PI3K in thymocyte survival
Wojciech Swat, Vivianne Montgrain, Teresa A Doggett, Jason Douangpanya, Kamal Puri, William Vermi, and Thomas G Diacovo*
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
ICOS Corporation, Bothell, WA, USA
Department of Pathology, University of Bresica, Bresica, Italy
Department of Pediatrics and Pathology, Columbia University, New York, NY, USA
* Corresponding author; email: td2142{at}columbia.edu.
Class I phosphoinositide 3-kinases (PI3Ks), consisting of PI3K ,  , and  , are a family of intracellular signalling molecules that play an important role in cell-mediated immune responses. In thymocytes, however, their role is less clear, although PI3K is postulated to partially contribute to pre-TcR-dependent differentiation. We now report that PI3K in conjunction with PI3K is required for thymocyte survival and ultimately T cell production. Surprisingly, genetic deletion of the both p110 and p110 catalytic subunits resulted in a dramatic reduction in thymic size, cellularity, and lack of cortico-medullary differentiation. Total thymocyte counts in these animals were 27-fold less than in wild-type (WT) controls due to a diminished number of CD4+CD8+ double-positive (DP) cells and was associated with T cell depletion in blood and secondary lymphoid organs. Moreover, this alteration in the DP population is intrinsic to thymocytes as reconstitution of p110-/-animals with WT fetal liver cells restored the proportions of all thymocyte populations to that in WT controls. The observed defects are related to massive apoptosis in the DP population, as TcR expression, pre-TcR selection, and generation of DP cells appeared relatively unperturbed. Thus, class I PI3Ks work in concert to protect developing thymocytes from apoptosis.
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