title: A fas antigen receptor mutation allows development of toxic shock syndrome toxin-1-induced lethal shock in V beta 8.2 T-cell receptor transgenic mice.
abstract: Recombinant toxic shock syndrome toxin-1 (rTSST-1) administered to MRL-lpr/lpr TCR V beta 8.2 transgenic mice at doses of 0.1 microgram/mouse resulted in 100% mortality. This was an unexpected finding since TSST-1 does not activate V beta 8.2 T cells. In contrast, control mice heterozygous at the lpr locus and also for the transgene (MRL-lpr/+; V beta 8.2/0) 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 hepatocellular necrosis) as well as substantially elevated serum TNF-alpha, 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 V beta 8.2 splenocytes revealed the presence of minor populations of TSST-1-reactive V beta elements (i.e. V beta 3 and V beta 15). Furthermore, an expansion of the V beta 3 and V beta 15 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 V beta 8.2 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 lpr mice. To test this hypothesis more directly, we compared the sensitivity of MRL-lpr/lpr mice (not carrying the V beta 8.2 transgene) to MRL-+/+ mice. The MRL-lpr/lpr fas antigen-defective mice were substantially more susceptible to rTSST-1 challenge. Mice carrying the lpr mutation on another genetic background (C57BL/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.
authors: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, OH 45267, USA.
authors: C M
authors: CM
authors: Cullen
authors: P F
authors: PF
authors: Bonventre
authors: H
authors: H
authors: Heeg
authors: H
authors: H
authors: Bluethmann
authors: J D
authors: JD
authors: Mountz
authors: C K
authors: CK
authors: Edwards
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins; D001483:Base Sequence; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D006579:Heterozygote; D007376:Interleukin-2 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009589:Nitrogen Oxides / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000209:etiology* / Q000473:pathology; D013154:Spleen / Q000166:cytology; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics*
chemical_list: C091566:3,4-dihydro-3,3-dimethylisoquinoline-N-oxide; C082151:3-(6-amino-9H-purin-9-yl)-cyclopentanol; D001427:Bacterial Toxins; D004768:Enterotoxins; D007376:Interleukin-2; D015850:Interleukin-6; D007546:Isoquinolines; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C030107:enterotoxin F, Staphylococcal; D019014:fas Receptor; D016572:Cyclosporine; D000225:Adenine