THE VAV-RAC1 PATHWAY IN CYTOTOXIC LYMPHOCYTES REGULATES THE GENERATION OF CELL-MEDIATED KILLING

The Rad guanine nucleotide exchange factor, Vav, is activated in hemat opoietic cells in response to a large variety of stimuli. The downstre am signaling events derived from Vav have been primarily characterized as leading to transcription or transformation. However, we report her e that Vav and Rad in natural killer (NK) cells regulate the developme nt of cell-mediated killing. There is a rapid increase in Vav tyrosine phosphorylation during the development of antibody-dependent cellular cytotoxicity and natural killing. In addition, overexpression of Vav, but not of a mutant lacking exchange factor activity, enhances both f orms of killing by NK cells. Furthermore, dominant-negative Rad inhibi ts the development of NK cell-mediated cytotoxicity by two mechanisms: (ci) conjugate formation between NK cells and target cells is decreas ed; and (b) those NK cells that do form conjugates have decreased abil ity to polarize their granules toward the target cell. Therefore, our results suggest that in addition to participating in the regulation of transcription, Vav and Rad are pivotal regulators of adhesion, granul e exocytosis, and cellular cytotoxicity.