title: The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells.
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.
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: G H
authors.initials: GH
authors.lastname: Wabnitz
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Balta
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schindler
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kirchgessner
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Jahraus
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Meuer
authors.affiliation: Institute of Immunology, Ruprecht-Karls-University , Im Neuenheimer Feld 305, Heidelberg D-69120, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Samstag