Separation of function between the domains of toxic shock syndrome toxin-1.
Toxic shock syndrome toxin-1 (TSST1) is a superantigenic exotoxin produced by certain strains of Staphylococcus aureus Structurally, TSST1 is composed of two domains: residues determined by crystallography to directly interact with MHC II molecules reside within the N-terminal domain, while TSST1 residues critical for superantigenicity are within the C-terminal domain. In this study, we expressed the individual N- and C-terminal domains of TSST1 in Escherichia coli and studied their biologic activities. The TSST1 N-terminal domain (TSST(1-87)) did not induce proliferation of human PBLs or release of TNF-beta, but did induce TNF-alpha release. However, TSST1-elicited proliferation and release of both TNF isoforms were inhibited by a molar excess of TSST(1-87). The TSST1 C-terminal domain (TSST(88-194)) did not bind MHC II molecules, yet it elicited production of TNF-alpha and TNF-beta, and induced TCR Vbeta-specific proliferation similarly to intact TSST1. When covalently cross-linked to tumor cells, TSST(88-194) elicited a local in vivo antitumor response indistinguishable from TSST1. Although intact TSST1 causes lethal shock in vivo, the individual domains of this molecule may have therapeutic potential: the N-terminal domain to antagonize lymphocyte activation and TNF release during acute TSST1-precipitated toxic shock syndrome, and the C-terminal domain to stimulate antitumor responses without MHC II binding.
Wahlsten
J L
JL
University of Minnesota, Department of Pharmacology, Minneapolis 55455, USA.
Ramakrishnan
S
S
D000818:Animals; D001427:Bacterial Toxins; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004768:Enterotoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000276:immunology; D013329:Structure-Activity Relationship; D018089:Superantigens; D014407:Tumor Cells, Cultured
D001427:Bacterial Toxins; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal