The capacity of the rabies virus superantigen (SAg) and the nucleocapsid (NC) to activate human tonsil lymphocytes was analyzed by studying the capacity of NC to cause lymphocytes to proliferate and secrete Ig and cytokines. NC activation was compared to that obtained with the Staphylococcus-derived SAg, SEE, and TSST-1. Despite a weak T lymphocyte mitogenic activity restricted to CD4+ T cells, NC triggers tonsil B lymphocytes to produce IgG in quantities and frequencies similar to those of SEE and TSST-1. In the same way as these two SAg, NC induces IgG production only in the presence of T cells and optimally with a T/B ratio of 1/5. However, unlike SEE and TSST-1, NC does not trigger IgM production. The pattern of cytokines produced upon NC activation, IL-4 and IL-10, weak IL-2 production, and no IFN-gamma, suggests that rabies SAg stimulates Th2 rather than Th1 lymphocytes. In contrast, the pattern of cytokines produced upon TSST-1 activation, IL-2, IFN-gamma, and no IL-4, suggests that TSST-1 induces rather a Th1 response. The specific Th2 triggering by NC could explain the unique capacity of the rabies SAg to increase the in vivo antibody response to a simultaneously injected antigen.