Superstimulatory influenza virus and highly organized BCR-ligands act synergistically on B cell activation

The influenza virus glycoprotein hemagglutinin (HA) behaves as a superstimulatory protein for B lymphocytes from various species. Polyclonal B cell stimulation mediated by HA can be blocked by soluble anti-Ig antibodies. We here report that, if presented in a highly organized form, i.e., as anti-Ig mAb coupled to dextran (anti-Ig-Dex), conventional BCR-ligands and influenza viruses act synergistically on murine B cell activation. Proliferative responses of both spellen-derived and peritoneal B cells mediated by suboptimal amounts of HA were significantly augmented by costimulation with anti-Ig-Dex, and vice versa. Similarly, anti-Ig-Dex, which on its own cannot induce Ig production in the absence of added cytokines, significantly enhanced Ig synthesis in response to superstimulatory HA. By contrast, poorly organized BCR-ligands (i.e. the same anti-Ig mAb in a soluble form) had either no, or a strong inhibitory effect on virus-triggered lymphocyte activation. Assays with various second messenger-antagonists, however, revealed clear differences in the signaling pathway employed by anti-Ig-Dex and HA, suggesting that the functional synergy between the two multimeric agents is mediated by engagement of distinct transducing elements. Taken together, these results indicate that the superstimulatory function of influenza virus HA represents a molecular strategy to mimick B cell activation by conventional, highly organized particulate-antigens.