Vav regulates peptide-specific apoptosis in thymocytes

The protooncogene Vav functions as a GDP/GTP exchange factor (GEF) for Rho- like small GTPases involved in cytoskeletal reorganization and cytokine pro duction in T cells. Gene-targeted mice lacking Vav have a severe defect in positive and negative selection of T cell antigen receptor transgenic thymo cytes in vivo, and vav(-/-) thymocytes are completely resistant to peptide- specific and anti-CD3/anti-CD28-mediated apoptosis. Vav acts upstream of mi te chondrial pore opening and caspase activation. Biochemically, Vav regula tes peptide-specific Ca2+ mobilization and actin polymerization. Peptide-sp ecific cell death was blocked both by cytochalasin D inhibition of actin po lymerization and by inhibition of protein kinase C (PKC). Activation of PKC with phorbol ester restored peptide-specific apoptosis in vav(-/-) thymocy tes. Vav was found to bind constitutively to PKC-theta in thymocytes. Our r esults indicate that peptide-triggered thymocyte apoptosis is mediated via Vav activation, changes in the actin cytoskeleton, and subsequent activatio n of a PKC isoform.