The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation

Phosphatidylinositol 3- kinases (PI3Ks) play a critical role in regulating B cell receptor - and T cell receptor - mediated signaling. However, their role in natural killer (NK) cell development and functions is not well understood. Using mice expressing p110 delta(D910A), a catalytically inactive p110 delta, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27(High) NK numbers. p110 delta inactivation marginally impaired NK-mediated cytotoxicity against tumor cells in vitro and in vivo. However, NKG2D, Ly49D, and NK1.1 receptor - mediated cytokine and chemokine generation by NK cells was severely affected in these mice. Further, p110 delta(D910A/D910A) NK cell mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110 delta(D910A/D910A) NK cells had a reduced c-Jun N-terminal kinase 1/2 phosphorylation in response to NKG2D-mediated activation. These results reveal a previously unrecognized role of PI3K-p110 delta in NK cell development and effector functions.