Binding of Superantigen Toxins into the CD28 Homodimer Interface Is Essential for Induction of Cytokine Genes That Mediate Lethal Shock

Arad, Gila; Levy, Rachel; Nasie, Iris; Hillman, Dalia; Rotfogel, Ziv; Barash, Uri; Supper, Emmanuelle; Shpilka, Tomer; Minis, Adi; Kaempfer, Raymond

doi:10.1371/journal.pbio.1001149

Cited by 129 publications

(253 citation statements)

References 39 publications

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“…2) inhibited inflammatory cytokine gene expression in human peripheral blood mononuclear cells (PBMC) in the absence of any superantigen, induced by anti-CD28/anti-CD3 monoclonal antibodies, which models the normal T cell-mediated immune response, or by anti-CD28 alone, yet not by anti-CD3 alone [13] . We considered the intriguing possibility that the peptide might compete with the anti-CD28 antibody for its binding site in CD28 and by extension, that the intact superantigen molecule might bind directly to CD28.…”

Section: Cd28 Is An Obligatory Receptor For Superantigensmentioning

confidence: 99%

“…To test this concept, we next screened a random phage display library for peptides that bind to CD28 and are displaced from CD28 by SEB. Indeed, such peptides could be recovered; they strongly inhibited SEB-mediated induction of inflammatory cytokines in human PBMC and protected mice from lethal SEB challenge [13] . Confocal microscopy then showed that labeled SEB colocalizes fully with CD28 expressed on the surface of CD28-transfected cells, providing a strong indication that even in the absence of MHC-II and TCR, the superantigen will bind directly to the extracellular domain of the CD28 receptor [13] .…”

Section: Cd28 Is An Obligatory Receptor For Superantigensmentioning

confidence: 99%

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Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

2017

Receptor Clin Invest

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Formation of the costimulatory axis between the B7-2 and CD28 coreceptors is critical for T-cell activation.Superantigens, Gram-positive bacterial virulence factors, cause toxic shock and sepsis by hyperinducing inflammatory cytokines. We report a novel role for costimulatory receptors CD28 and B7-2 as obligatory receptors for superantigens, rendering them therapeutic targets. We show that by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the interaction between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using a conserved twelve amino-acid domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, sites far removed from where these receptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces. Short B7-2 and CD28 dimer interface mimetic peptides bind diverse superantigens, prevent superantigen binding to cell-surface B7-2 or CD28, attenuate inflammatory cytokine overexpression, and protect mice from lethal superantigen challenge. Thus, superantigens induce a cytokine storm by mediating not only the interaction between MHC-II molecule and T-cell receptor but critically, by promoting B7-2/CD28 coreceptor engagement, forcing the principal costimulatory axis to signal excessively. Our findings highlight the B7/CD28 interaction as a bottleneck in signaling for expression of inflammatory cytokines. B7-2 and CD28 homodimer interface mimetic peptides prevent superantigen lethality by blocking the superantigen-host costimulatory receptor interaction.

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Section: Cd28 Is An Obligatory Receptor For Superantigensmentioning

confidence: 99%

Section: Cd28 Is An Obligatory Receptor For Superantigensmentioning

confidence: 99%

Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

2017

Receptor Clin Invest

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“…These toxins bind directly to the MHC class II molecules on APCs and the variable b-chains of the TCR, and activate the endogenous pathways dependent upon immune synapse formation (12,13). CD28, a costimulatory receptor on T cells, has been recently identified as a superantigen receptor (14). Concerted interaction of the superantigen with all three receptors (CD28, MHC class II, and TCR) allows stable synapse formation resulting in exceptionally robust T cell responses, particularly Th1 cytokine induction, and lethality (14).…”

mentioning

confidence: 99%

“…CD28, a costimulatory receptor on T cells, has been recently identified as a superantigen receptor (14). Concerted interaction of the superantigen with all three receptors (CD28, MHC class II, and TCR) allows stable synapse formation resulting in exceptionally robust T cell responses, particularly Th1 cytokine induction, and lethality (14). Via this mechanism, SEB activates ∼20% of the T cell population, whereas exposure to normal Ags activates ,0.01% of T cells (14,15).…”

mentioning

confidence: 99%

“…Concerted interaction of the superantigen with all three receptors (CD28, MHC class II, and TCR) allows stable synapse formation resulting in exceptionally robust T cell responses, particularly Th1 cytokine induction, and lethality (14). Via this mechanism, SEB activates ∼20% of the T cell population, whereas exposure to normal Ags activates ,0.01% of T cells (14,15). CTLA4 plays an important role in controlling excessive T cell activation (16).…”

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confidence: 99%

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Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology

Whitfield

Taylor

Risdall

et al. 2017

The Journal of Immunology

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Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p < 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p < 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.

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A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections

et al. 2014

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Binding of Superantigen Toxins into the CD28 Homodimer Interface Is Essential for Induction of Cytokine Genes That Mediate Lethal Shock

Abstract: Bacterial superantigen toxins bind directly to the dimer interface of CD28, the principal co-stimulatory receptor, to induce a lethal cytokine storm, and peptides that prevent this binding can suppress superantigen lethality.

Cited by 129 publications

References 39 publications

Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology

A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections

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