Defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help

Vav, a guanine nucleotide exchange factor for members of the Rho family of small GTPases, is activated through engagement of B and T lymphocyte antige n receptors. It is important for establishing the signaling threshold of th e TCR, as mice lacking Vav display defective thymocyte selection. Here, con ventional B cells are shown to develop normally in Vav-deficient mice but t hese mice have few B-1 B cells. The threshold for inducing B cell prolifera tion through BCR engagement in vitro is greater in Vav-deficient B cells. N evertheless, in vivo the mutant mice have normal antibody responses to hapt enated Ficoll. In contrast, Vav(-/-) mice show defective class switching to IgG and germinal center formation when immunized with haptenated protein. Interestingly, this defect is reversed in chimeras where normal T cells are present. Antigen-specific proliferation of T cells in the T zone was found to be similar in wildtype and Vav(-/-) mice but the induction of IL-4 mRNA and switch transcripts was specifically impaired. These results suggest th at defective immunoglobulin class switching in Vav-deficient mice is attrib utable to compromised T cell help.