The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells
Cytotoxic T-cells (CTLs) play an important role in many immune-mediated inflammatory diseases. Targeting cytotoxicity of CTLs would allow to interfere with immune-mediated tissue destruction. Here we demonstrate that WF-10, a pro-oxidative compound, inhibits CTL-mediated cytotoxicity. WF-10 did not...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
25 July 2016
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| In: |
Cell death discovery
Year: 2016, Jahrgang: 2, Heft: 1, Pages: 1-11 |
| ISSN: | 2058-7716 |
| DOI: | 10.1038/cddiscovery.2016.57 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/cddiscovery.2016.57 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/cddiscovery201657 
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| Verfasserangaben: | G. H. Wabnitz, E. Balta, S. Schindler, H. Kirchgessner, B. Jahraus, S. Meuer and Y. Samstag |
| Zusammenfassung: | Cytotoxic T-cells (CTLs) play an important role in many immune-mediated inflammatory diseases. Targeting cytotoxicity of CTLs would allow to interfere with immune-mediated tissue destruction. Here we demonstrate that WF-10, a pro-oxidative compound, inhibits CTL-mediated cytotoxicity. WF-10 did not influence early steps of target-cell killing, but impaired the ability of CTLs to detach from the initial target cell and to move to a second target cell. This reduced serial killing was accompanied by stronger enrichment of the adhesion molecule LFA-1 in the cytolytic immune synapse. LFA-1 clustering requires activation of the actin-bundling protein L-plastin and was accordingly diminished in L-plastin knockdown cells. Interestingly, WF-10 likely acts through regulating L-plastin: (I) It induced L-plastin activation through phosphorylation leading to enhanced LFA-1-mediated cell adhesion, and, importantly, (II) WF-10 lost its influence on target-cell killing in L-plastin knockdown cells. Finally, we demonstrate that WF-10 can improve immunosuppression by conventional drugs. Thus, while cyclosporine A alone had no significant effect on cytotoxicity of CTLs, a combination of cyclosporine A and WF-10 blocked target-cell killing synergistically. Together, our findings suggest that WF-10 - either alone or in combination with conventional immunosuppressive drugs - may be efficient to control progression of diseases, in which CTLs are crucially involved. |
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| Beschreibung: | Gesehen am 04.06.2020 |
| Beschreibung: | Online Resource |
| ISSN: | 2058-7716 |
| DOI: | 10.1038/cddiscovery.2016.57 |