Essential role of PI3Kδ and PI3Kγ in thymocyte survival

Class 1 phosphoinositide 3-kinases (PI3Ks), consisting of PI3Kα, β, γ, and δ, are a family of intracellular signaling molecules that play important roles in cell-mediated immune responses. In thymocytes, however, their role is less clear, although PI3Kγ is postulated to partially contribute to pre-TCR-dependent differentiation. We now report that PI3Kδ, in conjunction with PI3Kγ, is required for thymocyte survival and ultimately for T-cell production. Surprisingly, genetic deletion of the p110δ and p110γ catalytic subunits resulted in a dramatic reduction in thymus size, cellularity, and lack of corticomedullary differentiation. Total thymocyte counts in these animals were 27-fold lower than in wild-type (WT) controls because of a diminished number of CD4⁺CD8⁺ double-positive (DP) cells and were associated with T-cell depletion in blood and in secondary lymphoid organs. Moreover, this alteration in the DP population was intrinsic to thymocytes, because the reconstitution of p110γδ ^-/- animals with WT fetal liver cells restored the proportions of all thymocyte populations to those in WT controls. The observed defects were related to massive apoptosis in the DP population; TCRB expression, pre-TCR selection, and generation of DP cells appeared relatively unperturbed. Thus, class 1 PI3Ks work in concert to protect developing thymocytes from apoptosis.