Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation

Superantigens trigger an excessive cellular immune response, leading to tox ic shock. We have designed a peptide antagonist that inhibits superantigen- induced expression of human genes for interleukin-2, gamma interferon and t umor necrosis factor-b, which are cytokines that mediate shock. The peptide shows homology to a b-strand-hinge-a-helix domain that is structurally con served in superantigens, yet is remote from known binding sites for the maj or histocompatibility class II molecule and T-cell receptor. Superantigens depend on this domain for T-cell activation. The peptide protected mice aga inst lethal challenge with staphylococcal and streptococcal superantigens. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly de veloped protective antibodies against superantigen that rendered them resis tant to further lethal challenges, even with different superantigens. Thus, the lethal effect of superantigens can be blocked with a peptide antagonis t that inhibits their action at the beginning of the toxicity cascade, befo re activation of T cells takes place.