A novel system to study the effects of cc-cross-linking CD23/Fc epsilon RII and sig on murine B lymphocytes utilizes a highly multivalent form of anti-lg prepared by covalently linking anti-Ig antibodies to a DNP-dextran backbone. CD23-slg co-cross-linking is accomplished by the addition of DNP-specific monoclonal IgE, Previous studies demonstrated that co-cross-linking CD23 and sig significantly inhibited mouse B cell proliferation, especially at high doses of the multivalent anti-tg. interestingly examination of early activation signals reveals no difference in a cells subjected to cc-cross-linking conditions as compared to B cells activated with anti-lg alone, Total cellular protein tyrosine phosphorylation levels are unchanged by co-cross-linking. Analysis of B cell mRNA reveals that co-cross-linking the receptors does not alter the expression levels of ornithine decarboxylase 8 h after stimulation as compared to the controls, In contrast, revels of the protooncogene c-myc were significantly elevated 1 h after inducing a cell activation under co-crosslinking conditions, However, it remains unclear whether this aberrant c-myc regulation plays any role in inducing apoptosis. In addition, on day 3 after stimulation, the co-cross-linking of CD23 and sig resulted in the formation of apoptotic a cells, determined by both photomicroscopy of the B cell cultures and FAGS analysis of B cell nuclei. B cells obtained from bcl-2 transgenic mice proliferated as well as controls, and failed to undergo apoptosis when CD23 and sig were co-crosslinked on their surface, These studies indicate that co-cross-linking of CD23 with a cell sig inhibits B cell proliferation by a mechanism that is distinct from that seen by co-cross-linking of the Fc gamma RII and sig, In addition, these results suggest a means by which antigen-specific IgE can downregulate additional B cell activation and IgE synthesis.