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

Abstract

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.

Vav1: a key signal transducer downstream of the TCR

“…The difference in the ability of Vav1-deficient T cells to proliferate in vivo vs. in vitro may be due to the presence of costimulatory signals in the lymphoid organ, which are absent in a simplified in vitro proliferation assay. In other studies, examination of antiviral responses in Vav1-deficient mice showed decreased primary CD8 cytotoxic T cell responses, although these became normal following secondary restimulation in vitro (39).…”

Vav-1 regulates NK T cell development and NK cell cytotoxicity

“…Vav-1 -/-mice have reduced numbers of both T and NK T cells, as well as defects in primary cytotoxic T cell responses [24]. Therefore, to generate Vav-1 -/-LAK populations comparable to wild type, before culture we first depleted CD4 + and CD8 + cells from the spleen.…”

Suboptimal engagement of the T‐cell receptor by a variety of peptide–MHC ligands triggers T‐cell anergy

“…[46][47][48][49][50] Vav-deficient T cells were shown to be defective in TCR-induced actin polymerization. 51,52 Low densities of agonist peptides or short-lived peptides induced a transient phosphorylation of Vav in T cells treated with inhibitory doses of peptides, which was accompanied by no detectable actin polymerization.…”