ID: 35: The dimer interfaces of B7-2 and CD28 receptors control their engagement and signaling and are effective therapeutic targets for lethal cytokine storm

Abstract

We created peptides that protect broadly against severe, life-threatening infections and reveal a novel and critical regulatory role for costimulatory receptor homodimer interfaces in inflammatory T-cell hyperactivation. Our finding is that the interaction between B7-2 and CD28, primary costimulatory receptors that are expressed constitutively, can be controlled through their dimer interfaces and presents a novel, broad-spectrum host-oriented target for harmful inflammatory cytokine responses (“cytokine storm”). Excessive induction of inflammatory cytokines by Gram-positive bacterial superantigens, we show, strictly requires their direct binding into the homodimer interfaces of CD28 and its coligand, B7-2. By binding the dimer interface of both receptors, superantigens potently enhance B7-2/CD28 engagement and signaling, to induce a cytokine storm. Short peptide mimetics of the B7-2 or CD28 dimer interface bind diverse superantigens, prevent binding of superantigen to cell-surface B7-2 or CD28, attenuate superantigen-induced overexpression of IFN- γ , TNF- α and IL2 in human PBMC, and are effective antagonists in vivo, protecting mice from lethal superantigen challenge. B7-2 and CD28 dimer interfaces thus serve as novel therapeutic targets for superantigen intoxication. Surprisingly, when used in pathologies unrelated to superantigens, peptide mimetics of either the CD28 or B7-2 dimer interface potently attenuate the inflammatory cytokine storm, by directly inhibiting B7-2/CD28 engagement. In human PBMC, these peptides inhibit induction of inflammatory cytokines by lipopolysaccharide, a hallmark of Gram-negative infection, or by monoclonal antibodies that signal through CD28. Such host-oriented peptides protect mice from lethal avian H5N1 and pandemic H1N1 influenza virus infection while strongly reducing inflammatory cytokine levels.