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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 62 citations

PubMed: 36638190 DOI: 10.1126/sciimmunol.abq0178

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.

Sci Immunol 8(79):eabq0178

Authors: Kelsey Voss, Allison E Sewell, Evan S Krystofiak, Katherine N Gibson-Corley, Arissa C Young, Jacob H Basham, Ayaka Sugiura, Emily N Arner, William N Beavers, Dillon E Kunkle, Megan E Dickson, Gabriel A Needle, Eric P Skaar, W Kimryn Rathmell, Michelle J Ormseth, Amy S Major, Jeffrey C Rathmell

Affiliations

  • Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • Division of Comparative Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN, USA.
  • Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN, USA.

Abstract

T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for T1 and inhibitory for induced regulatory T cells (iT). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited T1 and T17 cells yet enhanced iT. In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on T17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.

MeSH

Cells, Transferrin, Pathology, Lupus Erythematosus, Systemic, Receptors, Transferrin, T-Lymphocytes

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