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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 downstream 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-/- 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 important effector molecule that relays antigen receptor signaling to IL-2 production and activation of cytotoxic T cells.

Original publication

DOI

10.1002/(SICI)1521-4141(199905)29:05<1709::AID-IMMU1709>3.0.CO;2-O

Type

Journal article

Journal

Eur J Immunol

Publication Date

05/1999

Volume

29

Pages

1709 - 1718

Keywords

Animals, CD28 Antigens, Interleukin-2, Mice, Mice, Knockout, Oncogene Proteins, Proto-Oncogene Proteins c-vav, Receptor-CD3 Complex, Antigen, T-Cell, T-Lymphocytes, Cytotoxic