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* Department of Immunology and Oncology, Centro Nacional de Biotecnología, and
Centro de Biología Molecular, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma, Cantoblanco, Madrid, Spain;
Hospital Puerta de Hierro, San Martín de Porres, Madrid, Spain;
Department of Genetics, Biology, and Biochemistry, University of Torino, Turin, Italy; and
¶
Institute of Biochemistry, University of Fribourg, Fribourg, Switzerland
The signaling pathways that control T cell differentiation have only begun to be elucidated. Using T cell lines, it has been shown that class IA phosphatidylinositol 3-kinase (PI3K), a heterodimer composed of a p85 regulatory and a p110 catalytic subunit, is activated after TCR stimulation. Nonetheless, the contribution of p85/p110 PI3K isoforms in T cell development has not been described. Mice deficient in the other family of class I PI3K, p110
, which is regulated by G protein-coupled receptors, exhibit reduced thymus size. Here we examine T cell development in p110-deficient mice and in mice expressing an activating mutation of the p85 regulatory subunit, p65PI3K, in T cells. We show that p110-deficient mice have a partial defect in pre-TCR-dependent differentiation, which is restored after expression of the p65PI3K activating mutation. Genetic alteration of both PI3K isoforms also affects positive selection; p110 deletion decreased and p65PI3K expression augmented the CD4+/CD8+ differentiation ratio. Finally, data are presented showing that both PI3K isoforms influenced mature thymocyte migration to the periphery. These observations underscore the contribution of PI3K in T cell development, as well as its implication in determining the CD4+/CD8+ T cell differentiation ratio in vivo.
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