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Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Kaempfer, Raymond Popugailo, Andrey Levy, Revital Arad, Gila Hillman, Dalia Rotfogel, Ziv |
| Copyright Year | 2017 |
| Abstract | 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.14800/rci.1500 |
| PubMed reference number | 28286804 |
| Journal | Medline |
| Volume Number | 4 |
| Issue Number | 1 |
| Alternate Webpage(s) | http://www.smartscitech.com/index.php/rci/article/download/1500/pdf |
| Alternate Webpage(s) | https://doi.org/10.14800/rci.1500 |
| Journal | Receptors & clinical investigation |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
