The guanine-nucleotide exchange factor Vav is a crucial regulator of B cell receptor activation and B cell responses to nonrepetitive antigens

The proto-oncogene product Vav is required for receptor clustering, prolife ration, and differentiation of T cells, and Vav was identified as a substra te in the TCR and B cell receptor signaling pathway. The role of Vav in B c ell responses to Ag challenge in vivo is not known. In this study, we show that Vav regulates B cell proliferation following in vitro activation of Ag receptors, but Vav has no apparent role in CD40-, IL-4-, or LPS-induced B cell activation. Increased degrees of Ag receptor cross-linking can partial ly reverse the proliferative defect in the anti-IgM response of vav(-/-) B cells, In vivo, vav(-/-) mice mounted protective antiviral IgM and IgG resp onses to infections with vesicular stomatitis virus and recombinant vaccini a virus expressing the vesicular stomatitis virus glycoprotein, which harbo r repetitive surface epitopes that directly cross-link the Ag receptor and activate B cells in the absence of T cell help. vav(-/-) B cells also respo nded normally to the polyvalent, repetitive hapten Ag trinitrophenyl (TNP)- Ficoll that effectively cross-links B cell receptors, However, vav(-/-) mic e failed to mount immune responses to the nonrepetitive, T cell-dependent h apten Ag (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP)-OVA. These results pr ovide the first genetic evidence on the role of the guanine exchange factor Vav in immune responses to viral infections and antigenic challenge in viv o, and suggest that Vav adjusts the threshold for Ag receptor-mediated B ce ll activation depending on the nature of the Ag.