CD46/CD3 costimulation induces morphological changes of human T cells and activation of Vav, Rac, and extracellular signal-regulated kinase mitogen-activated protein kinase

Efficient T cell activation requires at least two signals, one mediated by the engagement of the TCR-CD3 complex and another one mediated by a costimu latory molecule. We recently showed that CD46, a complement regulatory rece ptor for C3b as well as a receptor for several pathogens, could act as a po tent costimulatory molecule for human T cells, highly promoting T cell prol iferation. Indeed, we show in this study that CD46/CD3 costimulation induce s a synergistic activation of extracellular signal-related kinase mitogen-a ctivated protein kinase. Furthermore, whereas T lymphocytes primarily circu late within the bloodstream, activation may induce their migration toward s econdary lymphoid organs or other tissues to encounter APCs or target cells . In this study, we show that CD46/CD3 costimulation also induces drastic m orphological changes of primary human T cells, as well as actin relocalizat ion. Moreover, we show that the GTP/GDP exchange factor Vav is phosphorylat ed upon CD46 stimulation alone, and that CD46/CD3 costimulation induces a s ynergistic increase of Vav phosphorylation. These results prompted us to in vestigate whether CD46/CD3 costimulation induced the activation of GTPases from the Rho family. Indeed, we report that the small GTPase Rac is also ac tivated upon CD46/CD3 costimulation, whereas no change of Rho and Cdc42 act ivity could be detected. Therefore, CD46 costimulation profoundly affects T cell behavior, and these results provide important data concerning the bio logy of primary human T cells.