文章基本信息

标题：Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells
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作者：Man Lyang Kim ; Melinda Y. Hardy ; Laura E. Edgington-Mitchell 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：12
页码：1-20
DOI：10.1016/j.isci.2021.103509
语种：English
出版社：Elsevier
摘要：SummaryAlthough hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation. HCQ's effects did not require endo-lysosomal pH change, nor impaired autophagosome-lysosome fusion. We explored the clinical relevance of these findings in patients with celiac disease—a prototypic CD4 T-cell-mediated disease—and found that HCQ limitsex vivoantigen-specific T cell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease.Graphical abstractDisplay OmittedHighlights•HCQ inhibits proliferation of human CD4 T-cells without affecting early activation•HCQ dysregulates mitochondrial superoxide production in activated CD4 T-cells•Dysregulated ROS impairs autophagic flux in activated CD4 T-cells•HCQ limits antigen-specific T cell responses in patients with celiac diseaseex vivoMolecular biology; Immune system; Proteomics