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.