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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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Main Authors: Wabnitz, Guido H. (Author) , Balta, Emre (Author) , Schindler, S. (Author) , Kirchgessner, Henning (Author) , Jahraus, Beate (Author) , Meuer, Stefan (Author) , Samstag, Yvonne (Author)
Format: Article (Journal)
Language:English
Published: 25 July 2016
In: Cell death discovery
Year: 2016, Volume: 2, Issue: 1, Pages: 1-11
ISSN:2058-7716
DOI:10.1038/cddiscovery.2016.57
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/cddiscovery.2016.57
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/cddiscovery201657
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Author Notes:G. H. Wabnitz, E. Balta, S. Schindler, H. Kirchgessner, B. Jahraus, S. Meuer and Y. Samstag

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520 |a 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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