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

Thursday, June 23, 2022

3:15 PM – 3:30 PM PT

Location: Salons 3/4

Authors: Kelsey Voss, PhD (Presenting Author) - Vanderbilt University Medical Center; Arissa Young, MD (Co-Author) - Vanderbilt University Medical Center; Katherine Gibson-Corley, DVM, PhD, DACVP (Co-Author) - Vanderbilt University Medical Center; Allison Sewell, n/a (Co-Author) - Vanderbilt University Medical Center; Evan Krystofiak, PhD (Co-Author) - Vanderbilt University Medical Center; Jacob Basham, MD (Co-Author) - Vanderbilt University Medical Center; William Beavers, PhD (Co-Author) - Vanderbilt University Medical Center; Ayaka Suguira, BS (Co-Author) - Vanderbilt University; Eric Skaar, PhD, MPH (Co-Author) - Vanderbilt University Medical Center; Michelle Ormseth, MD (Co-Author) - Vanderbilt University Medical Center; Amy Major, PhD (Co-Author) - Vanderbilt University Medical Center; Jeffrey Rathmell, PhD (Co-Author) - Vanderbilt University Medical Center

Presenting Author(s)

KV

Kelsey Voss, PhD

Postdoctoral Fellow
Vanderbilt University Medical Center
Nashville, Tennessee, United States

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Chair(s)

Irini Sereti, MD

Senior Investigator- Section Chief
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland, United States

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/Cas9 screen identified the 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 and prolonged in T cells from SLE-prone mice which accumulated iron. Treatment of T cells from SLE-prone mice with a CD71 blocking antibody reduced intracellular iron and mTORC1 signaling and restored mitochondrial physiology. While Th1 cells were inhibited, CD71 blockade enhanced iTreg and their FoxP3 expression. In vivo this treatment reduced kidney and liver pathology, reduced CD4 T cells, and increased IL-10+ T cells in SLE-prone mice. Importantly, disease severity in patients with SLE correlated with CD71 expression on T cells and blocking CD71 enhanced IL-10 secretion. Excess iron uptake via CD71 dysregulation thus contributes to T cell dysfunction and can be targeted to correct SLE-associated pathology.