Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction

Superantigens—bacterial virulence factors—cause toxic shock by hyperinducing inflammatory cytokines. T-cell activation is mediated both by antigen and by interaction between principal costimulatory receptors B7-2 and CD28. Superantigens must bind CD28 to elicit cytokine overexpression through a hitherto unknown mechanism. We show that, by binding not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the B7-2/CD28 interaction, thereby inducing T-cell hyperactivation. Superantigens engage B7-2 and CD28 at their homodimer interfaces, far from where the receptors interact, demonstrating the regulatory properties of these interfaces. B7-2 dimer interface peptides attenuate cytokine overexpression and prevent superantigen lethality by blocking costimulatory receptor engagement by superantigen. Thus, bacterial superantigens induce a pathogenic "cytokine storm" by strongly enhancing formation of the B7-2/CD28 costimulatory axis.