The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

• Verfasst von: Wabnitz, Guido H. [VerfasserIn]
• Verfasst von: Balta, Emre [VerfasserIn]
• Verfasst von: Schindler, S. [VerfasserIn]
• Verfasst von: Kirchgessner, Henning [VerfasserIn]
• Verfasst von: Jahraus, Beate [VerfasserIn]
• Verfasst von: Meuer, Stefan [VerfasserIn]
• Verfasst von: Samstag, Yvonne [VerfasserIn]
• Titel: The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells
• Verf.angabe: G. H. Wabnitz, E. Balta, S. Schindler, H. Kirchgessner, B. Jahraus, S. Meuer and Y. Samstag
• E-Jahr: 2016
• Jahr: 25 July 2016
• Umfang: 11 S.
• Illustrationen: Illustrationen, Diagramme
• Fussnoten: Gesehen am 04.06.2020
• Titel Quelle: Enthalten in: Cell death discovery
• Ort Quelle: London : Nature Publishing Group, 2015
• Jahr Quelle: 2016
• Band/Heft Quelle: 2(2016), 1, Seite 1-11
• ISSN Quelle: 2058-7716
• DOI: doi:10.1038/cddiscovery.2016.57
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1699816336

Abstract

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.