T Cell Development Requires the Combined Activities of the p110 gamma and p110delta Catalytic Isoforms of Phosphatidylinositol 3-Kinase

摘要

The role of PI3K activity in T lymphocyte development is obscure because mice deficient in single PI3K catalytic subunits either die before birth(p110alpha~(-/-)and p110beta~(-/-))or lack a significant T cell developmentalphe-notype(p110gamma~(-/-)and p110delta~(-/-)).We have generated mice deficient in both p110gamma and p110delta and show that p110gamma/delta~(-/-)mice have a profound block in T cell development that occurs at the ^-selection checkpoint.We show thatpre-TCR-induced signaling is significantly reduced in p110gamma/delta~(-/-)thymocytes and that this results in a concomitant lack of proliferative expansion and increased apo-ptosis.The survival defect in p110gamma/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 Junction of p110gamma and p10dewlta.