MRL-lpr/lpr mice are defective in the fas Ag/APO-1 apoptosis gene (CD95). Using the hepatotoxin D-galactosamine (D-GalNH2), we demonstrate that MRL- lpr/lpr mice have an increased susceptibility to staphylococcal enterotoxin B (SEB)-induced lethal shock, which causes them to exhibit the septic shock- like behaviors of fur ruffling and listlessness, and death occurs within 8 to 18 h. SEB susceptibility is greater in Vβ8.2 TCR transgenic MRL-lpr/lpr mice than in nontransgenic mice. In studies designed to elucidate the molecular pathways of SEB-induced septic shock, we found that C57Bl/6.A(bo)/A(bo), MHC class II-deficient 'C2D' mice, but not C57Bl/6-+/+ mice, are nonresponsive to challenge with SEB. C2D mice, backcrossed with the fas mutation resulting in double-knockout C2D;lpr/lpr mice, are more susceptible to challenge with SEB/D-GalNH2. The LD50s for C57Bl/6.C3H-gld/gld 'fas ligand-mutant mice' challenged with SEB/D-GalNH2 were comparable to C57Bl/6.MRL-lpr/lpr and MRL- lpr/lpr mice, suggesting that reciprocal mutations in either fas or fas ligand increases susceptibility to bacterial superantigens (SAGs). SEB- induced lethal shock can be reversed by treatment with Abs to Vβ8 TCR, MHC class II Ia-+, IL-2, and TNF-α, by the immunosuppressant cyclosporin A, or by treatment with carbocyclic nucleoside analogues. These data indicate that SAG-induced septic shock is dependent on interactions with the TCR and MHC class II Ags, and they also suggest a critical role for a functional fas and/or fas ligand in resistance to SAG-induced septic shock.