title: Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction.
abstract: Full T-cell activation requires interaction between the costimulatory receptors B7-2 and CD28. By binding CD28, bacterial superantigens elicit harmful inflammatory cytokine overexpression through an unknown mechanism. We show that, by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the avidity between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using the same 12-aa β-strand-hinge-α-helix domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, areas remote from where these coreceptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces. Short B7-2 dimer interface mimetic peptides bind diverse superantigens, prevent superantigen binding to cell-surface B7-2 or CD28, attenuate inflammatory cytokine overexpression, and protect mice from lethal superantigen challenge. Thus, superantigens induce a cytokine storm not only by mediating the interaction between MHC-II molecule and T-cell receptor but also, critically, by promoting B7-2/CD28 coreceptor engagement, forcing the principal costimulatory axis to signal excessively. Our results reveal a role for B7-2 as obligatory receptor for superantigens. B7-2 homodimer interface mimotopes prevent superantigen lethality by blocking the superantigen-host costimulatory receptor interaction.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Levy
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Rotfogel
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Dalia
authors.initials: D
authors.lastname: Hillman
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Andrey
authors.initials: A
authors.lastname: Popugailo
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Gila
authors.initials: G
authors.lastname: Arad
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Supper
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Farhat
authors.initials: F
authors.lastname: Osman
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel kaempfer@hebrew.edu.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kaempfer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051940:B7-2 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004768:Enterotoxins / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D018089:Superantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D051940:B7-2 Antigen; D018106:CD28 Antigens; D016207:Cytokines; D004768:Enterotoxins; D018836:Inflammation Mediators; D010455:Peptides; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C031818:enterotoxin B, staphylococcal
keywords: B7-2 dimer interface; costimulatory receptor; cytokine storm; superantigen