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-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C1
,¶
* Department of Microbiology and Immunology, University of Western Ontario,
Lawson Health Research Institute,
Federation of Clinical Immunology Societies (FOCIS) Centre for Clinical Immunology and Immunotherapeutics, and Robarts Research Institute, London, Ontario, Canada;
Department of Research Service, Veterans Affairs Medical Center, Mid-South Center for Biodefense and Security, University of Tennessee Health Science Center, Memphis, TN 38163;
¶ Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45627; and
|| Boston Biomedical Research Institute, Watertown, MA 02472
Superantigens (SAgs) are microbial toxins that bind to both TCR β-chain variable domains (Vβs) and MHC class II molecules, resulting in the activation of T cells in a Vβ-specific manner. It is now well established that different isoforms of MHC II molecules can play a significant role in the immune response to bacterial SAgs. In this work, using directed mutational studies in conjunction with functional analyses, we provide a complete functional map of the low-affinity MHC II 
-chain binding interface of the SAg streptococcal pyrogenic exotoxin C (SpeC) and identify a functional epitope in the β-barrel domain that is required for the activation of T cells. Using cell lines that exclusively express individual MHC II isoforms, our studies provide a molecular basis for the selectivity of SpeC-MHC II recognition, and provide one mechanism by how SAgs are capable of distinguishing between different MHC II alleles.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Canadian Institutes of Health Research (CIHR) operating grants to J.K.M. and J.M. and National Institutes of Health Grant AI55882 to E.J.S. Stipend support to K.K. and A.K.M.N.R. was provided in part by scholarships from the Schulich School of Medicine and Dentistry and by an Early Research Award from The Ontario Ministry of Research and Innovation. Laboratory infrastructure was supported by a New Opportunities Fund award from the Canadian Foundation for Innovation and the Ontario Innovation Trust (to J.K.M). J.M. holds a Tier I Canada Research Chair in Immunobiology, and J.K.M. holds a New Investigator award from CIHR.
2 Address correspondence and reprint requests to Dr. John K. McCormick, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail address: john.mccormick{at}schulich.uwo.ca
3 Abbreviations used in this paper: SAg, superantigen; BLS, bare lymphocyte syndrome; MHC, MHC II -chain; MHCβ, MHC II β-chain; SE, staphylococcal enterotoxin; SEA/SEB/SEC3/SEE, staphylococcal exotoxin A, B, C3, or E; SpeA/SpeC, streptococcal pyrogenic exotoxin A or C; SSA, streptococcal superantigen; TEV, tobacco etch virus; TSST-1, toxic shock syndrome toxin-1; Vβ, variable region of the TCR β-chain.
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