Superantigens, like staphylococcal enterotoxin B (SEB), induce a strong proliferative response followed by clonal deletion of a substantial portion of defined Vbeta T cells. The remaining cells display in vitro anergy. We found that the immune response to SEB was paralleled by biphasic changes in the activity of the sympathetic nervous system. Furthermore, sympathetic denervation resulted in decreased SEB-induced cell proliferation and IL-2 production, and impeded the specific deletion of splenic CD4Vbeta8 cells observed in intact animals without affecting anergy. These studies provide the first evidence of an immunoregulatory cross-talk between sympathetic nerves and superantigen-activated immune cells.