Broad-Spectrum Peptide Antagonists of Superantigen Toxins

Abstract

Bacterial superantigens are among the most lethal of toxins. These stable proteins bind directly to most major histocompatibility (MHC) class II molecules and stimulate virtually all T cells bearing particular domains in the variable portion of the β-chain of the αβ T cell receptor (TCR), without need for processing by antigen-presenting cells. The peptides are capable of protecting mice from the lethal effects of superantigen toxins as widely different as staphylococcal enterotoxins (SE) SEB and toxic shock syndrome toxin 1 (TSST-1), and they can rescue animals already deeply into toxic shock. The superantigen antagonist peptides described in this chapter protect or rescue mice from lethal shock in a molar excess of as low as 20 fold over the toxin, implying that they bind tightly to a cellular target that is critical for superantigen action. The antagonist peptides described in the chapter provide a new molecular tool for understanding the mechanism of excessive human immune response activation by superantigens that occurs during toxic shock and for the identification of a novel target ligand that may interact with this superantigen domain. Removal of two amino acids from the dodecamer motif led to a significant decline in antagonist activity; this truncation may affect conformational stability or appropriate folding onto this putative receptor and reduce its affinity for the target.