Phospholipase C-γ2 is a critical signaling mediator for murine NK cell activating receptors

Phospholipase C-gamma (PLC gamma) is a key regulator of intracellular Ca2+ mobilization. Two isoforms of PLC gamma have been identified, PLC gamma 1 and PLC gamma 2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLC gamma 2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLC gamma 2 is more important than PLC gamma 1 for NK cell activation and whether PLC gamma 2 is also critical for NK cell development, secretion of IFN-gamma, and clearance of viral infections in vivo is not known. In this study, we report that PLC gamma 2 is the predominant isoform expressed in murine NK cells. PLC gamma 2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLC gamma 2-deficient NK cells exhibited a dramatic impairment of cytolytic function and IFN-gamma production upon ligation of activating receptors, whereas they did secrete IFN-gamma in response to cytokines. Consequently, mice lacking PLC gamma 2 controlled murine CMV infection substantially less effectively than did wild-type animals, and this defect was most evident in the spleen, where viral clearance mostly depends on NK cell lytic function. These results demonstrate that PLC gamma 2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.