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.
Highlights
T-cells are activated in lymph nodes through interaction with antigen-pres0enting cells (APCs)
We have recently shown that a pro-oxidative milleu influences the actin-reorganizing protein cofilin, thereby interfering with activation of naïve human T-cells.[8,24,25]
WF-10 is a compound that is stable in aqueous solution and is converted to chloramins in cellular environments (Supplementary Figure S1)
Summary
T-cells are activated in lymph nodes through interaction with antigen-pres0enting cells (APCs) This activation is initiated at the contact zone between T-cells and corresponding APCs, called immune synapse.[1] We identified regulators of the actin cytoskeleton that are important to initiate and to sustain the immune synapse, that is, cofilin and L-plastin.[2,3,4,5] While the actindepolymerizing molecule cofilin induces actin dynamics,[6,7] L-plastin regulates actin bundles and LFA-1 avidity within the immune synapse.[4] This T-cell intrinsic regulation of the immune synapse is modulated by extrinsic factors of the microenvironment. We have shown earlier that oxidative stress, as induced by H2O2, provokes an immediate inhibition of T-cell activation through a miss-regulation of the actin cytoskeleton and immune synapse formation.[2,8] a pro-oxidative microenvironment has the potential to switch the behavior of immunocompetent cells from an inflammatory into a tolerogenic or anergic state by regulating the functional plasticity of T-cells
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