Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling

Vav-1 and Vav-2 are closely related Dbl-homology CTP exchange factors (GEFs ) for Rho GTPases. Mutation of Vav-1 disrupts T cell development and T cell antigen receptor-induced activation, but has comparatively little effect o n B cells. We found that combined deletion of both Vav-1 and Vav-2 in mice resulted in a marked reduction in mature B lymphocyte numbers. Vav-1(-/-)Va v-2(-/-) B cells were unresponsive to B cell antigen receptor (BCR)-driven proliferation in vitro and to thymus-independent antigen in vivo. BCR-stimu lated intracellular calcium mobilization was greatly impaired in Vav1(-/-)V av-2(-/-) B cells. These findings establish a role for Vav-2 in BCR calcium signaling and reveal that the Vav family of GEFs is critical to B cell dev elopment and function.