1. Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells
- Author
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Man Lyang Kim, Melinda Y. Hardy, Laura E. Edgington-Mitchell, Sri H. Ramarathinam, Shan Zou Chung, Amy K. Russell, Iain Currie, Brad E. Sleebs, Anthony W. Purcell, Jason A. Tye-Din, and Ian P. Wicks
- Subjects
Molecular biology ,Immune system ,Proteomics ,Science - Abstract
Summary: Although 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 limits ex vivo antigen-specific T cell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease. more...
- Published
- 2021
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