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2 Is a Critical Signaling Mediator for Murine NK Cell Activating Receptors1
* Department of Pathology and Immunology, and Department of Medicine and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110
Phospholipase C-
(PLC) is a key regulator of intracellular Ca2+ mobilization. Two isoforms of PLC have been identified, PLC1 and PLC2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLC2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLC2 is more important than PLC1 for NK cell activation and whether PLC2 is also critical for NK cell development, secretion of IFN-, and clearance of viral infections in vivo is not known. In this study, we report that PLC2 is the predominant isoform expressed in murine NK cells. PLC2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLC2-deficient NK cells exhibited a dramatic impairment of cytolytic function and IFN- production upon ligation of activating receptors, whereas they did secrete IFN- in response to cytokines. Consequently, mice lacking PLC2 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 PLC2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.
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