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Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation

Nature Medicine volume 6, pages 414–421 (2000)Cite this article

Abstract

Superantigens trigger an excessive cellular immune response, leading to toxic shock. We have designed a peptide antagonist that inhibits superantigen-induced expression of human genes for interleukin-2, gamma interferon and tumor necrosis factor-b, which are cytokines that mediate shock. The peptide shows homology to a b-strand–hinge–a-helix domain that is structurally conserved in superantigens, yet is remote from known binding sites for the major histocompatibility class II molecule and T-cell receptor. Superantigens depend on this domain for T-cell activation. The peptide protected mice against lethal challenge with staphylococcal and streptococcal superantigens. Moreover, it rescued mice undergoing toxic shock. Surviving mice rapidly developed protective antibodies against superantigen that rendered them resistant to further lethal challenges, even with different superantigens. Thus, the lethal effect of superantigens can be blocked with a peptide antagonist that inhibits their action at the beginning of the toxicity cascade, before activation of T cells takes place.

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Figure 1: SEB agonist and antagonist activity of SEB-related peptides.
Figure 2: p12(150–161) is an antagonist of SEB.
Figure 3: Structures of superantigens.
Figure 4: Broad-spectrum superantigen antagonist activity of p12(150–161) and of antibodies raised against it.
Figure 5: Antagonist peptide protects and rescues mice from superantigen-induced lethal shock.
Figure 6: Mice protected by antagonist rapidly develop broad-spectrum immunity to lethal shock.

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Acknowledgements

The authors thank L. Zisu of the Bletterman Macromolecular Research Laboratory of the Hebrew University-Hadassah Medical School for synthesis of peptides, Y. Banai for assistance, M. Katzenellenbogen for help in determination of TNF-β mRNA, and H. Bercovier and S. Brocke for a review of the manuscript.

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  1. Department of Molecular Virology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel

    Gila Arad, Revital Levy, Dalia Hillman & Raymond Kaempfer

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  1. Gila Arad
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  2. Revital Levy
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Correspondence to Raymond Kaempfer.

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Arad, G., Levy, R., Hillman, D. et al. Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation. Nat Med 6, 414–421 (2000). https://doi.org/10.1038/74672

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