I03 Bacterial superantigens co-opt CD28 as their receptor and key transducer of lethal cytokine storm

Abstract

CD28 is a homodimer expressed constitutively on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands. Hitherto, CD28 was not known to bind microbial components yet our finding is that bacterial superantigen toxins co-opt CD28 as their receptor and that to induce a cytokine storm comprised mainly of IL2, IFN- γ and TNF- α , the superantigen must bind, in addition to its classical ligands, MHC II and T cell receptor, directly into the homodimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality. The interaction can be blocked with peptides that mimic the contact domains in superantigen or CD28. These peptides, we show, attenuate inflammatory cytokine gene induction and thus protect animals from lethal toxic shock. We elucidated the molecular mechanism of inflammatory cytokine storm underlying toxic shock, and used structural insight to design antagonists, one of which is now in a multi-center Phase II clinical trial against streptococcal toxic shock. We thus identify the CD28 homodimer interface as a critical receptor target for superantigens and key transducer of lethal cytokine storm. Our finding that CD28 is a receptor for the superantigen toxins broadens the scope of microbial pathogen recognition mechanisms and provides a novel approach for designing therapeutics that protect against the harmful effects of an inflammatory cytokine storm. Supported by DARPA, USAMRMC and a Biodefense Challenge Grant from NIAID.