Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells
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, Ian P. Wicks
Abstract
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.