Kinase activity of phosphoinositide 3‐kinase gamma is needed for T cell development, activation and chemotaxis

Abstract

Phosphoinositide 3‐kinase gamma (PI3Kγ) catalyzes the production of phosphatidylinositol‐3,4,5‐triphosphate by phosphorylating phosphatidylinositol (PI), phosphatidylinositol‐4‐ phosphate (PIP) and phosphatidylinositol‐4,5‐bisphosphate (PIP2). Catalytic subunit of PI3Kγ is activated by βγ subunits of heterotrimeric G proteins in response to chemokines, growth factors and hormones, which in turn coordinates cell migration, cell growth, cell cycle entry, and cell survival. PI3Kγ has been implicated in T cell function, but direct effect of its kinase function has not been evaluated. Using mice expressing a catalytically inactive mutant of PI3Kγ(PI3KγKD/KD) we were able to demonstrate that defect in kinase activity leads to T cell developmental defect in the thymus and results in decreased peripheral T cell numbers. PI3KγKD/KD peripheral CD4 and CD8 T cells demonstrated impaired TCR/CD28‐induced proliferation and IL‐2 production, reduced chemokine driven chemotaxis and impaired T cell differentiation. Thus, our study demonstrated that kinase activity of PI3Kγ amend status of T cell response by contributing to thymic development, T cell activation and differentiation as well as lymphocyte chemotaxis.