TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway

CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen activated protein kinases (MAPKs) and cell cycle progression throug h G(1). Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent re cruitment of the Vav GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF complexes, an event critical for Ag receptor-trigger ed T cell activation. Here, we show that TCR/CD28 costimulation synergistic ally induces Rac-1 GDP/GTP exchange. Our findings, obtained by using ZAP-70 -negative Jurkat T cells, indicate that CD28 costimulation augments TCR-med iated T cell activation by increasing the ZAP-70-mediated Tyr phosphorylati on of Vav. This event regulates the Rac-1-associated GTP/GDP exchange activ ity of Vav and downstream pathway(s) leading to PAK-1 and p38 MAPK activati on. CD28 amplifies TCR-induced ZAP-70 activity and association of Vav with ZAP-70 and linker for activation of T cells (LAT), These results favor a mo del in which ZAP-70 regulates the intersection of the TCR and CD28 signalin g pathways, which elicits the coupling of TCR and CD28 to the Rac-1, PAK-1, and p38 MAPK effector molecules.