Abstract
Staphylococcal and streptococcal superantigens are virulence factors that cause toxic shock by hyperinducing inflammatory cytokines. Effective T-cell activation requires interaction between the principal costimulatory receptor CD28 and its two coligands, B7-1 (CD80) and B7-2 (CD86). To elicit an inflammatory cytokine storm, bacterial superantigens must bind directly into the homodimer interfaces of CD28 and B7-2. Recent evidence revealed that by engaging CD28 and B7-2 directly at their dimer interface, staphylococcal enterotoxin B (SEB) potently enhances intercellular synapse formation mediated by B7-2 and CD28, resulting in T-cell hyperactivation. Here, we addressed the question, whether diverse bacterial superantigens share the property of triggering B7-2/CD28 receptor engagement and if so, whether they are capable of enhancing also the interaction between B7-1 and CD28, which occurs with an order-of-magnitude higher affinity. To this end, we compared the ability of distinct staphylococcal and streptococcal superantigens to enhance intercellular B7-2/CD28 engagement. Each of these diverse superantigens promoted B7-2/CD28 engagement to a comparable extent. Moreover, they were capable of triggering the intercellular B7-1/CD28 interaction, analyzed by flow cytometry of co-cultured cell populations transfected separately to express human CD28 or B7-1. Streptococcal mitogenic exotoxin Z (SMEZ), the most potent superantigen known, was as sensitive as SEB, SEA and toxic shock syndrome toxin-1 (TSST-1) to inhibition of inflammatory cytokine induction by CD28 and B7-2 dimer interface mimetic peptides. Thus, superantigens act not only by mediating unconventional interaction between MHC-II molecule and T-cell receptor but especially, by strongly promoting engagement of CD28 by its B7-2 and B7-1 coligands, a critical immune checkpoint, forcing the principal costimulatory axis to signal excessively. Our results show that the diverse superantigens use a common mechanism to subvert the inflammatory response, strongly enhancing B7-1/CD28 and B7-2/CD28 costimulatory receptor engagement.
Highlights
Bacterial superantigens are potent virulence factors secreted by Staphylococcus aureus and Streptococcus pyogenes that induce toxic shock by activating a cellular immune response, orders of magnitude greater than that elicited by regular antigens, leading to an ’inflammatory cytokine storm’
We originally reported that in staphylococcal enterotoxin B (SEB), this sequence folds into a short βstrand(8)/hinge/α-helix(4) domain that is far removed from the domains that bind the classical superantigen receptors, major histocompatibility class II (MHC-II) molecule and T-cell receptor (TCR), and is located on the opposite side of the superantigen protein molecule (14)
We examined whether the ability of SEB to promote B7-2/CD28 receptor engagement is shared by other bacterial superantigens
Summary
Bacterial superantigens are potent virulence factors secreted by Staphylococcus aureus and Streptococcus pyogenes that induce toxic shock by activating a cellular immune response, orders of magnitude greater than that elicited by regular antigens, leading to an ’inflammatory cytokine storm’. More recent work revealed that T-cell activation by superantigens requires, in addition, their direct binding to the principal costimulatory receptors, CD28 (4) and its coligand, B7-2 (CD86) (5). Together, these superantigen engagements result in a massive induction of inflammatory cytokines that mediate toxic shock, including interleukin-2, interferon-γ (IFN-γ) and tumor necrosis factor. Expressed constitutively on T cells, CD28 is a homodimer that interacts with its B7 coligands expressed on antigen-presenting cells, transducing the signal essential for T cell activation (7–10). Whereas B7-2 is expressed constitutively, CD28 coligand B7-1 (CD80) is induced gradually during the course of an immune response (10, 11); the B7-2/CD28 interaction transmits the earliest signal induced by an antigen (12, 13)
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