Vav-1 regulates NK T cell development and NK cell cytotoxicity.
The hematopoietic-specific Rho-family GTP exchange factor Vav-1 is a regulator of lymphocyte antigen receptor signaling and mediates normal maturation and activation of B and T cells. Recent findings suggest that Vav-1 also forms part of signaling pathways required for natural and antibody dependent cellular cytotoxicity (ADCC) of human NK cells. In this study, we show that Vav-1 is also expressed in murine NK cells. Vav-1(-/-) mice had normal numbers of splenic NK cells, and these displayed a similar expression profile of NK cell receptors as wild-type mice. Unexpectedly, IL-2-activated Vav-1(-/-) NK cells retained normal ADCC. Fc-receptor mediated activation of ERK, JNK, and p38 was also normal. In contrast, Vav-1(-/-) NK cells exhibited reduced natural cytotoxicity against EL4, C4.4.25, RMA and RMA/S. Together, the results demonstrate that Vav-1 is dispensable for mainstream NK cell development, but is required for NK natural cytotoxicity. Unlike the findings for NK cells, NK T cells were dramatically diminished in Vav-1(-/-) mice and splenocytes from Vav-1 mutant mice failed to produce IL-4 in response to in vivo CD3 stimulation. These data highlight the important role of Vav-1 in NK T cell development and NK cell function.
Chan
G
G
Abteilung Physiologische Chemie, Universität Ulm, Ulm, Germany.
Hanke
T
T
Fischer
K D
KD
D000818:Animals; D000906:Antibodies / Q000276:immunology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004789:Enzyme Activation; D017353:Gene Deletion; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG / Q000276:immunology
D000906:Antibodies; D018797:Cell Cycle Proteins; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; C496619:Vav1 protein, mouse; D020928:Mitogen-Activated Protein Kinases