The role of Vav family guanine nucleotide exchange factors and their substrates in B cell antigen receptor signaling

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B lymphocytes are central components of the immune system as they detect pathogens or pathogen-derived components such as bacterial toxins and respond with the production of protective antibodies. The recognition of foreign substances (antigens) is mediated by B cell antigen receptors (BCRs) expressed on the surface of mature B cells. Binding of antigen to the BCR initiates activation of intracellular signal transduction pathways that, together with further co-stimulatory signals, induce differentiation of the cells into antibody-producing plasma cells. The BCR-proximal signaling reactions involve a concerted interplay of cytosolic tyrosine kinases, adaptor proteins and lipid-modifying enzymes, which controls the production of lipid-derived second messengers and the subsequent rise in the intracellular concentration of Ca2+ ions. Furthermore, published work and our own preliminary data indicate a role of Vav protein family members in that process. Vav family proteins are generally considered to act as guanine nucleotide exchange factors for small G proteins of the Rho/Rac family and hence to control the activity of BCR-distal MAP kinase pathways. However, in the mouse Vav1 and Vav2 have been reported to be essential for BCR-proximal Ca2+ signaling as well. Yet, the biochemical mechanisms that underlie this observation remain unknown. Using TALEN-mediated genome editing we have generated a human B cell model system deficient for Vav1, which recapitulates the Ca2+ mobilization defect observed in B cells of Vav1/2 double-deficient mice. Reconstitution of Vav1-deficient human B cells with catalytically inactive Vav1 does not restore BCR-induced Ca2+ signaling. Together, the available data clearly indicate that BCR-induced Ca2+ mobilization is not only controlled by protein tyrosine kinases and phospholipid-converting enzymes as previously thought, but requires an additional class of enzymatic activity that is provided by Vav family guanine nucleotide exchange factors. In the proposed research project we want to characterize the molecular mechanisms by which Vav family proteins and their substrates, small G proteins of the Rho/Rac family, control BCR-proximal signaling processes that regulate B cell activation and differentiation of memory B cells into antibody-producing plasma cells. The results may provide a basis for the development of therapeutic approaches to manage B cell-associated diseases such as antibody-driven autoimmunity, allergies and B cell-derived malignancies.