Abstract
Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells 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. 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.
Highlights
Superantigens are pyrogenic exotoxins secreted by the ubiquitous Gram-positive bacterial strains, Staphylococcus aureus and Streptococcus pyogenes
The antigen-presenting cell (APC) presents the processed antigen through a pocket in its MHC-II molecule to a specific Vβ chain on the T-cell receptor (TCR) expressed on the surface of very few
This work reveals a novel role for CD28, hitherto thought to function solely as costimulatory receptor in the immune response, as a direct receptor of a class of microbial virulence factors, the superantigen toxins
Summary
Superantigens are pyrogenic exotoxins secreted by the ubiquitous Gram-positive bacterial strains, Staphylococcus aureus and Streptococcus pyogenes. Pioneering work by Marrack and others in the late 1980s and 1990s showed that the superantigen achieves this by binding directly, as intact protein, to the major histocompatibility class II (MHC-II) molecule on the antigen-presenting cell and the T-cell receptor (TCR) on the T-cell, without need for antigen processing and bypassing the restriction typical for conventional antigens [5,6,7]. The superantigen provides an intermolecular bridge between the MHC-II molecule and the TCR This classical view held for over two decades, until the recent discovery that in order to induce a potent, harmful inflammatory response, the superantigen toxin must bind, in addition, directly to a third receptor. We know that blocking access of the superantigen to CD28 is enough to provide protection from lethal toxic shock [8]
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