OX40 is a member of the TNFINGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells. In the present study, we show that cross-linking of OX4OL on CD40L-stimulated Bcells, algD dextran-stimulated Bcells, or both results in a significantly enhanced proliferative response with no change in the cell survival rate. Furthermore, OX40 stimulation increases immunoglobulln heavy chain mRNA levels and immunoglobulin secretion, which could not be blocked by anti-cytokine antibodies. In additlonal molecular studies, we show that OX4OL cross-linking results In the down-regulation of the tmnscrlption factor BSAP. This, in turn, leads to a change in the in vivo binding pattern of the Immunoglobulin heavy chain gene 3’a enhancer, suggesting its activation. This effect may thus be one mechanism for 0X40-induced Increase in immunoglobulin secretion. In conclusion, our data suggest that the 0X40-OX4OL interaction is a novel pathway in T cell-dependent B cell proliferation and differentiation.