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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, PLC
1 and PLC
2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLC
2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLC
2 is more important than PLC
1 for NK cell activation and whether PLC
2 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 PLC
2 is the predominant isoform expressed in murine NK cells. PLC
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
2-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 PLC
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
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.
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