Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio

Abstract

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, p110γ, which is regulated by G protein-coupled receptors, exhibit reduced thymus size. Here we examine T cell development in p110γ-deficient mice and in mice expressing an activating mutation of the p85 regulatory subunit, p65^PI3K, in T cells. We show that p110γ-deficient mice have a partial defect in pre-TCR-dependent differentiation, which is restored after expression of the p65^PI3K activating mutation. Genetic alteration of both PI3K isoforms also affects positive selection; p110γ deletion decreased and p65^PI3K 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.