Abstract
Phospholipase C-gamma (PLCgamma) is a key regulator of intracellular Ca(2+) mobilization. Two isoforms of PLCgamma have been identified, PLCgamma1 and PLCgamma2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLCgamma2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLCgamma2 is more important than PLCgamma1 for NK cell activation and whether PLCgamma2 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 PLCgamma2 is the predominant isoform expressed in murine NK cells. PLCgamma2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLCgamma2-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 PLCgamma2 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 PLCgamma2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Antigens, Ly / metabolism
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CHO Cells
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Cells, Cultured
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Cricetinae
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Cytotoxicity, Immunologic / genetics
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Herpesviridae Infections / enzymology
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Herpesviridae Infections / immunology
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Interferon-gamma / metabolism
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Isoenzymes / biosynthesis
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / physiology
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Killer Cells, Natural / enzymology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lectins, C-Type
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Lymphocyte Activation* / genetics
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Membrane Proteins / deficiency
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Membrane Proteins / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muromegalovirus / immunology
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Phospholipase C gamma
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Receptors, IgG / deficiency
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Receptors, IgG / physiology
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Receptors, Immunologic / biosynthesis
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology*
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Receptors, NK Cell Lectin-Like
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Type C Phospholipases / biosynthesis
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Type C Phospholipases / deficiency
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Type C Phospholipases / genetics
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Type C Phospholipases / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Ly
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Fcgr3 protein, mouse
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Hcst protein, mouse
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Isoenzymes
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Lectins, C-Type
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Membrane Proteins
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Receptors, IgG
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Receptors, Immunologic
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Receptors, NK Cell Lectin-Like
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Tyrobp protein, mouse
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Interferon-gamma
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Type C Phospholipases
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Phospholipase C gamma