The Journal of Experimental Medicine
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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 Coluccia, Eleftheria Rosmarakia, Søren Bregenholta, Sandrine I. Samsona, Vincenzo Di Bartolob, Martin Turnerc, Lesley Vanesd, Victor Tybulewiczd, and James P. Di Santoa

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
Laboratory for Cytokines and Lymphoid Development, Department of Immunology, The Pasteur Institute, 25 rue Dr. Roux, 75015 Paris France.33-1-4061-351033-1-4061-3664

cecco{at}pasteur.fr

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1–/– mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1–/– mice produced normal amounts of interferon (IFN)-{gamma} in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1–/– NK cells resulted in normal IFN-{gamma} production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1–/– NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-{gamma} production.

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

Abbreviations used in this paper: ADCC, antibody-dependent cell cytotoxicity; ERK, extracellular signal-regulated kinase; GEFs, guanine nucleotide exchange factors; L.m., Listeria monocytogenes; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3 kinase; PLC, phospholipase C.

© 2001 The Rockefeller University Press


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