Every adaptive immune response requires costimulation through the B7/CD28 axis, 
with CD28 on T-cells functioning as principal costimulatory receptor. 
Staphylococcal and streptococcal superantigen toxins hyperstimulate the 
T-cell-mediated immune response by orders of magnitude, inducing a lethal 
cytokine storm. We show that to elicit an inflammatory cytokine storm and 
lethality, superantigens must bind directly to CD28. Blocking access of the 
superantigen to its CD28 receptor with peptides mimicking the contact domains in 
either toxin or CD28 suffices to protect mice effectively from lethal shock. Our 
finding that CD28 is a direct receptor of superantigen toxins broadens the scope 
of microbial pathogen recognition mechanisms.