| Autor: |
Voss, Kelsey, Sewell, Allison E., Krystofiak, Evan S., Gibson-Corley, Katherine N., Young, Arissa C., Basham, Jacob H., Sugiura, Ayaka, Arner, Emily N., Beavers, William N., Kunkle, Dillon E., Dickson, Megan E., Needle, Gabriel A., Skaar, Eric P., Rathmell, W. Kimryn, Ormseth, Michelle J., Major, Amy S., Rathmell, Jeffrey C. |
| Zdroj: |
Science Immunology; 2023, Vol. 8 Issue 79, p1-18, 18p |
| Abstrakt: |
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 TH1 and inhibitory for induced regulatory T cells (iTregs). 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 TH1 and TH17 cells yet enhanced iTregs. 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 TH17 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. Ironing out T cell dysfunction: Systemic lupus erythematosus (SLE) is an autoimmune disease in which dysfunctional T cells display metabolic abnormalities. Voss et al. unravel mechanisms associated with the role of excess iron in dysfunctional T cells. A CRISPR screen identified a role for the transferrin receptor (CD71) in SLE-prone T cells. Activated T cells up-regulated CD71, which was enhanced in SLE-prone T cells due to altered endosomal recycling. Elevated CD71 promoted intracellular iron uptake, which impaired mitochondrial function and mTORC1 signaling, leading to TH17 differentiation and suppression of inducible Tregs. In contrast, anti-CD71 treatment reduced iron uptake, promoted IL-10 production by CD4 T cells, and reversed SLE symptoms in mice. Disease severity in SLE patients correlated with CD71 expression on TH17 cells. These findings highlight a role for CD71 in iron uptake by T cells that contributes to SLE pathology. —CNF [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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