A Requirement for the Rho-Family GTP Exchange Factor Vav in Positive and Negative Selection of Thymocytes

Abstract

The T cell repertoire is shaped by positive and negative selection of thymocytes that express low levels of T cell receptor (TCR) and both CD4 and CD8. TCR-mediated signals that determine these selection processes are only partly understood. Vav, a GDP-GTP exchange factor for Rho-family proteins, is tyrosine phosphorylated following TCR stimulation, suggesting that it may transduce TCR signals. We now demonstrate that mice lacking Vav are viable and display a profound defect in the positive selection of both class I- and class II-restricted T cells. In contrast, Vav is not essential for negative selection, though in its absence negative selection is much less effective. Vav may influence the efficiency of TCR-induced selection events by regulating the intracellular calcium flux of thymocytes.

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

“…Furthermore, up-regulation of the activation marker CD69 in response to peptide was similarly impaired in Vav1 -/-cells (not shown). This was consistent with previous observations that mutation of Vav1 reduces a number of TCR signaling pathways in thymocytes but does not completely abrogate them [6,14].…”

“…Firstly, we and others have shown that Vav1 transduces signals to the activation of PLC + 1 and thus to an intracellular calcium flux [6,10,11,13,14]. This flux in turn activates the calcium-dependent protease caspian, which is required for LFA-1 clustering [28].…”

“…Mice deficient in Vav1 show defective positive and negative selection of thymocytes, consistent with TCR signaling deficits [6,7]. Furthermore Vav1-deficient T cells are defective in TCR-induced proliferation and cytokine synthesis [8][9][10][11].…”

“…However, mutation of Vav1 abrogates positive selection of several transgenic TCR molecules, such that these mice contain almost no mature thymocytes or T cells bearing the monoclonal TCR [6,7]. Thus we chose to use CD4 + CD8 + double-positive (DP) thymocytes -a TCR-bearing population of cells preceding the positive-selection checkpoint -for these studies.…”

Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

“…Its expression is restricted to cells of haematopoietic origin (Katzav et al, 1989). Targeted gene disruption revealed the importance of Vav1 for receptor-mediated proliferation and TCR-mediated positive selection (Fischer et al, 1995;Tarakhovsky et al, 1995;Zhang et al, 1995;Turner et al, 1997). Vav1 is furthermore important for the reorganization of the cytoskeleton and actin polymerization which contributes to the clustering of TCRs into patches and caps Holsinger et al, 1998).…”