A Review on CD28: Direct and Critical Receptor for Superantigen Toxins

Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on Tcells
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. Superantigens are among the most stable proteins known: They resist heat and
survive boiling, protease digestion, as well as acid denaturation. 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.