Cutting edge:: T cell development requires the combined activities of the p110γ and p110δ catalytic isoforms of phosphatidylinositol 3-kinase

The role of PI3K activity in T lymphocyte development is obscure because mice deficient in single PI3K catalytic subunits either die before birth (p110 alpha(-/-) and p110 beta(-/-)) or lack a significant T cell developmental phenotype (p110 gamma(-/-) and p110 delta(-/-)). We have generated mice deficient in both p110 gamma and p110 delta and show that p110 gamma/delta(-/-) mice have a profound block in T cell development that occurs at the beta-selection checkpoint. We show that pre-TCR-induced signaling is significantly reduced in p110 gamma/delta(-/-) thymocytes and that this results in a concomitant lack of proliferative expansion and increased apoptosis. The survival defect in p110 gamma/delta(-/-) thymocytes is associated with increased levels of the pro-apoptotic molecule BcL2 interacting mediator of cell death. This work demonstrates that PI3K activity is critical for T cell development and depends on the combined function of p110 gamma and p110 delta.