Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.
Kelsey VossAllison E SewellEvan S KrystofiakKatherine N Gibson-CorleyArissa C YoungJacob H BashamAyaka SugiuraEmily N ArnerWilliam N BeaversDillon E KunkleMegan E DicksonGabriel A NeedleEric P SkaarW Kimryn RathmellMichelle J OrmsethAmy S MajorJeffrey C RathmellPublished in: Science immunology (2023)
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 T H 1 and inhibitory for induced regulatory T cells (iT regs ). 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 T H 1 and T H 17 cells yet enhanced iT regs . 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 T H 17 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.
Keyphrases
- systemic lupus erythematosus
- disease activity
- regulatory t cells
- nk cells
- iron deficiency
- rheumatoid arthritis
- poor prognosis
- cell surface
- type diabetes
- genome wide
- high throughput
- oxidative stress
- reactive oxygen species
- adipose tissue
- cell death
- climate change
- risk assessment
- drug induced
- insulin resistance
- genome editing