Functional dichotomy in natural killer cell signaling: Vav1-dependent and -independent mechanisms.
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.
Colucci
F
F
Laboratory for Cytokines and Lymphoid Development, Pasteur Institute, 75015 Paris, France. cecco@pasteur.fr
Rosmaraki
E
E
Bregenholt
S
S
Samson
S I
SI
Di Bartolo
V
V
Turner
M
M
Vanes
L
L
Tybulewicz
V
V
Di Santo
J P
JP
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; C496619:Vav1 protein, mouse; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium