p110γ and p110δ phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells

Phosphoinositide 3-kinases (PI-3Ks) are key enzymes for cell development, activation, and survival. Here we showed that PI-3K class IB and class IA catalytic subunits, p110 gamma and p110 delta, played a crucial role in the development and functions of murine NK cells. p110 gamma deficiency and impairment of G protein-coupled receptor (GPRC) signaling prevented full NK cell maturation. Concomitant loss of p110 gamma and p110 delta exacerbated this defect, resulting in a very small population of NK cells with a highly immature phenotype in the bone marrow and periphery. Moreover, combined p110 gamma and p110 delta signals were required for cytotoxicity and activation of the kinase ERK during NK cell-target cell interaction. p110 gamma played a major role in receptor-induced interferon-gamma (IFN-gamma) production through a pathway that involved the kinase ERK and 5-Lipoxigenase, which most likely generates lipid mediators activating GPRCs. Conversely, P13Ks negatively regulated interleukin-12 (IL-12) and IL-18-induced IFN-gamma by modulating p38 kinase activation. Our data shed light on the multiple intersecting pathways through which P13Ks; control NK cell-mediated innate responses.