Enterotoxins produced by Staphylococcus aureus are potent mitogens for human T cells and cause lethal toxic shock. These superantigens bind to major histocompatibility complex class II on antigen-presenting cells outside the conventional peptide-binding groove and stimulate T cells expressing certain T-cell receptor V beta gene products. We investigated other cell-surface molecules on human peripheral blood mononuclear cells that can mediate staphylococcal enterotoxin B (SEB)-induced T-cell proliferation and cytokine production. SEB-induced proliferation of T cells was inhibited by monoclonal antibodies to CD2, CD11a, CD18, CD28, CD44, CD58 and ICAM-1. Anti-ICAM-1 also blocked the production of pro-inflammatory mediators, TNF alpha and IFN gamma by SEB-stimulated T cells. These data suggest that the surface molecules, CD11a:CD18/ICAM-1, CD2/CD58, CD28 and CD44, are all important co-receptors for T-cell activation by superantigens. Thus, like conventional antigens, multiple stimulatory signals from the interactions of these receptors are required for superantigen-induced immune responses. Reducing toxic mediators such as TNF alpha and IFN gamma by anti-ICAM antibodies in SEB-induced T-cell responses may be a useful therapeutic strategy to circumvent SEB toxicity and pathogenesis.