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-mediated cytoskeletal reorganization required for receptor clustering, proliferation and thymic selection. Moreover, Vav has been identified as a major substrate in the CD28 signal transduction pathway and overexpression of Vav enhances TCR-mediated IL-2 secretion in T cells. Here we show that CD3- plus CD28-mediated proliferation and IL-2 production were reduced in vav gene- deficient T cells. However, Vav had no apparent role in phorbol 12-myristate 13-acetate- plus CD28-mediated proliferation and IL-2 production, suggesting that Vav acts down- stream of the TCR/CD3 complex. In vivo, Vav expression was crucial to generate primary vesicular stomatitis virus (VSV)-specific cytotoxic T cell responses. In contrast, vav n/n mice exhibited a reduced but significant footpad swelling after lymphocytic choriomeningitis virus (LCMV) 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 first genetic evidence that Vav is an impor- tant effector molecule that relays antigen receptor signaling to IL-2 production and activation of cytotoxic T cells.