title: Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.
abstract: Bacterial superantigens, a diverse family of toxins, induce an inflammatory cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands, yet we show here that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality. Mice were protected from lethal superantigen challenge by short peptide mimetics of the CD28 dimer interface and by peptides selected to compete with the superantigen for its binding site in CD28. Superantigens use a conserved β-strand/hinge/α-helix domain of hitherto unknown function to engage CD28. Mutation of this superantigen domain abolished inflammatory cytokine gene induction and lethality. Structural analysis showed that when a superantigen binds to the T cell receptor on the T cell and major histocompatibility class II molecule on the antigen-presenting cell, CD28 can be accommodated readily as third superantigen receptor in the quaternary complex, with the CD28 dimer interface oriented towards the β-strand/hinge/α-helix domain in the superantigen. Our findings identify the CD28 homodimer interface as a critical receptor target for superantigens. The novel role of CD28 as receptor for a class of microbial pathogens, the superantigen toxins, broadens the scope of pathogen recognition mechanisms.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Gila
authors.initials: G
authors.lastname: Arad
authors.forename: Revital
authors.initials: R
authors.lastname: Levy
authors.forename: Iris
authors.initials: I
authors.lastname: Nasie
authors.forename: Dalia
authors.initials: D
authors.lastname: Hillman
authors.forename: Ziv
authors.initials: Z
authors.lastname: Rotfogel
authors.forename: Uri
authors.initials: U
authors.lastname: Barash
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Supper
authors.forename: Tomer
authors.initials: T
authors.lastname: Shpilka
authors.forename: Adi
authors.initials: A
authors.lastname: Minis
authors.forename: Raymond
authors.initials: R
authors.lastname: Kaempfer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology; D018604:Epitope Mapping; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology*; D020349:Surface Plasmon Resonance
chemical_list: D001427:Bacterial Toxins; D018106:CD28 Antigens; D016207:Cytokines; D004768:Enterotoxins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; C031818:enterotoxin B, staphylococcal