Function of PI3Kγ in Thymocyte Development, T Cell Activation, and Neutrophil Migration

TLDR

Phosphoinositide 3‑kinases regulate fundamental cellular responses such as proliferation, apoptosis, motility, and adhesion. Viable gene‑targeted mice lacking the p110 catalytic subunit of PI3Kγ were generated to study its function. PI3Kγ is essential for thymocyte survival and mature T‑cell activation, but not for B‑cell development; its deficiency impairs neutrophil chemotaxis and respiratory burst by disrupting GPCR‑induced PI(3,4,5)P₃ production and downstream Akt, S6K, and ERK signaling, thereby affecting thymocyte development, T‑cell activation, neutrophil migration, and oxidative burst.

Abstract

Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kγ were generated. We show that PI3Kγ controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kγ-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)–coupled receptor (GPCR) agonists and chemotactic agents. PI3Kγ links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kγ regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.