The oncogene product Vav is a crucial regulator of primary cytotoxic T cell responses but has no apparent role in CD28-mediated co-stimulation

The guanine nucleotide-exchange factor Vav is a regulator of antigen-mediat ed cytoskeletal reorganization required for receptor clustering, proliferat ion and thymic selection. Moreover, Vav has been identified as a major subs trate in the CD28 signal transduction pathway and overexpression of Vav enh ances TCR-mediated IL-2 secretion in T cells. Here we show that CD3- plus C D28-mediated proliferation and IL-2 production were reduced in vav gene-def icient T cells. However, Vav had no apparent role in phorbol 12-myristate 1 3-acetate-plus CD28-mediated proliferation and IL-2 production, suggesting that Vav acts downstream of the TCR/CD3 complex. In vivo, Vav expression wa s crucial to generate primary vesicular stomatitis virus (VSV)-specific cyt otoxic T cell responses. In contrast, vav(-/-) mice exhibited a reduced but significant footpad swelling after lymphocytic choriomeningitis virus (LCM V) infections and mounted a measurable primary cytotoxic T cell response to LCMV. Upon in vitro restimulation, cytotoxic T cell responses of both VSV- and LCMV-infected mice reached near normal levels. Our data provide the fi rst genetic evidence that Vav is an important effector molecule that relays antigen receptor signaling to IL-2 production and activation of cytotoxic T cells.