HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsGila Arad, Revital Levy, Iris Nasie, Dalia Hillman, Ziv Rotfogel, Uri Barash, Emmanuelle Supper, Tomer Shpilka, Adi Minis, Raymond Kaempfer
JournalPLoS biology (PLoS Biol) Vol. 9 Issue 9 Pg. e1001149 (Sep 2011) ISSN: 1545-7885 [Electronic] United States
PMID21931534 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Bacterial Toxins
  • CD28 Antigens
  • Cytokines
  • Enterotoxins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Superantigens
  • enterotoxin F, Staphylococcal
  • enterotoxin B, staphylococcal
Topics
  • Amino Acid Sequence
  • Animals
  • Bacterial Toxins (immunology)
  • CD28 Antigens (genetics, immunology)
  • Cell Line, Tumor
  • Cytokines (genetics, immunology)
  • Enterotoxins (immunology)
  • Epitope Mapping
  • Escherichia coli (genetics, metabolism)
  • Female
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Immunity, Cellular
  • Leukocytes, Mononuclear (cytology, immunology)
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Antigen, T-Cell (immunology)
  • Recombinant Fusion Proteins (genetics, immunology)
  • Shock, Septic (genetics, immunology)
  • Staphylococcus aureus (genetics, immunology)
  • Superantigens (administration & dosage, immunology)
  • Surface Plasmon Resonance

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: