Dysregulated Transferrin Receptor Disrupts T Cell Iron Homeostasis to Drive Inflammation in Systemic Lupus Erythematosus

T cells in systemic lupus erythematosus (SLE) exhibit mitochondrial abnormalities including elevated oxidative stress. Because excess iron can promote these phenotypes, we tested iron regulation of SLE T cells. A CRISPR screen identified Transferrin Receptor (CD71) as important for Th1 cells but detrimental for induced regulatory T cells (iTreg). Activated T cells induce CD71 to increase iron uptake, but this was exaggerated in T cells from SLE-prone mice which accumulated iron. Treatment of T cells from SLE-prone mice with CD71 blocking antibody reduced intracellular iron and mTORC1 signaling and restored mitochondrial physiology. While Th1 cells were inhibited, CD71 blockade enhanced iTreg. In vivo this treatment reduced pathology and increased IL-10 in SLE-prone mice. Importantly, disease severity correlated with CD71 expression on SLE patient T cells and blocking CD71 enhanced IL-10 secretion. Excess T cell iron uptake thus contributes to T cell dysfunction and can be targeted to correct SLE-associated pathology. ### Competing Interest Statement J.C.R. is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics, a scientific advisory board member and stockholder of Caribou Biosciences, a member of the scientific advisory board of Nirogy Therapeutics, has consulted for Merck, Pfizer, and Mitobridge within the past three years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. K.V. and J.C.R. have filed a provisional patent application entitled: CD71-blocking Antibodies for Treating Autoimmune and Inflammatory Diseases (U.S. Provisional Patent Application No: 63/274,297).