Functional Dichotomy in Natural Killer Cell Signaling: Vav1-Dependent and -Independent Mechanisms

doi:10.1084/jem.193.12.1413

Published online 18 June 2001.

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© The Rockefeller University Press, 0022-1007/2001/6/1413/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 12, June 18, 2001 1413-1424

Original Article

Functional Dichotomy in Natural Killer Cell Signaling: Vav1-Dependent and -Independent Mechanisms

Francesco Colucci^a, Eleftheria Rosmaraki^a, Søren Bregenholt^a, Sandrine I. Samson^a, Vincenzo Di Bartolo^b, Martin Turner^c, Lesley Vanes^d, Victor Tybulewicz^d, and James P. Di Santo^a
^a Laboratory for Cytokines and Lymphoid Development, Pasteur Institute, 75015 Paris, France
^b Laboratory for Molecular Immunology, Pasteur Institute, 75015 Paris, France
^c The Babraham Institute, Cambridge CB2 4AT, United Kingdom
^d The National Institute for Medical Research, London NW7 1AA, United Kingdom

Correspondence to: Francesco Colucci, Laboratory for Cytokines and Lymphoid Development, Department of Immunology, The Pasteur Institute, 25 rue Dr. Roux, 75015 Paris France. Tel:33-1-4061-3664 Fax:33-1-4061-3510 E-mail:cecco{at}pasteur.fr.

The product of the protooncogene Vav1 participates in multiplesignaling pathways and is a critical regulator of antigen–receptorsignaling in B and T lymphocytes, but its role during in vivonatural killer (NK) cell differentiation is not known. Herewe have studied NK cell development in Vav1^-^/- mice and foundthat, in contrast to T and NK-T cells, the absolute numbersof phenotypically mature NK cells were not reduced. Vav1^-^/-mice produced normal amounts of interferon (IFN)- ${gamma}$ in responseto Listeria monocytogenes and controlled early infection butshowed reduced tumor clearance in vivo. In vitro stimulationof surface receptors in Vav1^-^/- NK cells resulted in normalIFN- ${gamma}$ production but reduced tumor cell lysis. Vav1 was foundto control activation of extracellular signal-regulated kinasesand exocytosis of cytotoxic granules. In contrast, conjugateformation appeared to be only mildly affected, and calcium mobilizationwas normal in Vav1^-^/- NK cells. These results highlight fundamentaldifferences between proximal signaling events in T and NK cellsand suggest a functional dichotomy for Vav1 in NK cells: a rolein cytotoxicity but not for IFN- ${gamma}$ production.

Key Words: tumor clearance, Listeria infection, exocytosis, lymphoid development,cytokines

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