Recombinant toxic shock syndrome toxin-1 (rTSST-1) administered to MRL-Ipr/lprLCR Vβ8.2 transgenic mice at doses of 0.1 µg/mouse resulted in 100% mortality. This was an unexpected finding since TSST-1 does not activate Vβ8.2 T cells. In contrast, control mice heterozygous at the Ipr locus and also for the transgene (MRL-lpr/+·, Vβ8.2/0) survived doses of superantigen 100 times higher. The transgenic mice which succumbed to rTSST-1 challenge exhibited histopathology of the liver consistent with toxic shock (generalized inflammation and hepatocellualr necrosis) as well as substantially elevated serum TNF-α, IL-2, and IL·6 cytokine levels. Splenic T cells derived from transgenic mice stimulated with rTSST-1 in vitro did not undergo detectable proliferation as measured in a standard mitogen assay. However, PCR amplification of cDNA prepared from the Vβ8.2 splenocytes revealed the presence of minor populations of TSST-1 -reactive Vβ elements (i.e. Vβ3 and Vβl5). Furthermore, an expansion of the Vβ3 and Vβl5 T-cell families was detected by PCR assay of spleen cell cultures stimulated with rTSST-1. These results suggested that the exquisite sensitivity of the MRL-lpr/lpr Vβ8.2 transgenic animals to rTSST-1 was not dependent exclusively on T-cell proliferation but was augmented by the influence of a defective fas antigen receptor expressed in homozygous Ipr mice. To test this hypothesis more directly, we compared the sensitivity of MRL-lpr/lpr mice (not carrying the Vβ8.2 transgene) to MRL·+/+ mice. The MRL-lpr/lpr fas antigen-defective mice were substantially more susceptible to rTSST-1 challenge. Mice carrying the Ipr mutation on another genetic background (C51BL/6.C3H-lpr/lpr) were also more sensitive to rTSST-1 challenge than were C57BL/6.C3H-+/+ mice. Although induction of toxic shock is clearly associated with T-cell proliferation, defects in fas antigen receptor or ligand may also contribute substantively to superantigen-mediated lethal shock by still undefined mechanisms. © 1996 S. Karger AG, Basel.