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 Blood, 1 February 2006, Vol. 107, No. 3, pp. 994-1002.
Prepublished online as a Blood First Edition Paper on October 4, 2005; DOI 10.1182/blood-2005-06-2428.

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Submitted June 20, 2005
Accepted September 18, 2005

Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells

Anouk Caraux, Nayoung Kim, Sarah E Bell, Simona Zompi, Thomas Ranson, Sarah Lesjean-Pottier, Marcos E Garcia-Ojeda, Martin Turner, and Francesco Colucci*

Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France; Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom

* Corresponding author; email: francesco.colucci{at}bbsrc.ac.uk.

Phospholipase C-gamma2 (PLC{gamma}2) is a key component of signal transduction in leukocytes. In Natural killer (NK) cells, PLC{gamma}2 is pivotal for cellular cytotoxicity, however it is not known which steps of the cytolytic machinery it regulates. We found that PLC{gamma}2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing centre, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC{gamma}2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self MHC class I, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, Ly49H. Defective secretion was specific to cytotoxic granules, because release of interferon-{gamma} upon stimulation with Interleukin-12 was normal. PLC{gamma}2-/- mice could not reject MHC Class I-deficient lymphoma cells, nor could they control cytomegalovirus infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization towards targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC{gamma}2 regulates selective facets of innate immunity, as it is essential for NK cell responses to malignant and virally infected cells, but not to bacterial infections.


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