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.