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

Journal article

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.

Authors: Penninger, J; Fischer, K; Sasaki, T; Kozieradzki, I; Le, J

• Publication status: Published
• Journal: European journal of immunology
• Volume: 29
• Issue: 5
• Pages: 1709-1718
• Publication date: 1999-05-01
• DOI: 10.1002/(sici)1521-4141(199905)29:05<1709::aid-immu1709>3.3.co;2-f
• EISSN: 1521-4141
• ISSN: 0014-2980
• Language: English
• Keywords: Proto-Oncogene Proteins c-vav; T-Lymphocytes, Cytotoxic; Mice, Knockout; Oncogene Proteins; Interleukin-2; Antigens, CD28; Mice; Receptor-CD3 Complex, Antigen, T-Cell; Animals