Iron deprivation restrains the differentiation and pathogenicity of T helper 17 cell

Li, Lin; Yan, Xia; Yuan, Shijie; Li, Fēi; Xie, Xinyan; Luo, Yuan; Yang, Xun; He, Ran

doi:10.1002/jlb.3ma0821-015r

Cited by 13 publications

(7 citation statements)

References 45 publications

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“…Although anti-CD71 treatment did not affect the viability of T H 17 cells, anti-CD71 interfered with their differentiation, in agreement with other recent work ( 29 ). The percentage of IL-17 + cells was significantly reduced compared with controls (fig.…”

Section: Resultssupporting

confidence: 92%

“…In support of this, iron-deficient mice failed to develop experimental autoimmune encephalomyelitis (EAE) ( 63 ), and a CD4 T cell–specific deletion of Tfrc also failed to drive T H 17 neuroinflammation via decreased granulocyte-macrophage colony-stimulating factor mRNA stability ( 64 ). CD71 blockade was previously shown to inhibit T H 17 differentiation partly by increasing IL-2 secretion ( 29 ), but our T H 17 cell cultures did not produce significantly more IL-2 upon anti-CD71 treatment. T H 17 cultures from SLE-prone mice demonstrated a higher propensity for T H 17 cell differentiation, which was associated with altered expression of key iron metabolism genes.…”

Section: Discussioncontrasting

confidence: 67%

“…Low serum iron conditions can also impede the primary CD8 T cell response to vaccinations ( 25 ) and T H 1 responses ( 26 ). Regulation of iron metabolism may also differ among T cell subsets ( 27 ), because T H 1 cells were reported to be highly sensitive to iron depletion ( 28 ), and CD71 blockade inhibited T H 17 differentiation by increasing interleukin-2 (IL-2) expression and reducing recruitment of retinoic acid receptor (RAR)–related orphan receptor (RORγt) to the IL17a locus ( 29 ). In addition, elevated iron in SLE T cells was linked to epigenetic changes that promoted pathogenic T follicular helper (T FH ) differentiation ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultssupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…Previous study demonstrated that peroxiredoxin six overexpression eliminated high-glucose induced ferroptosis, which was reflected in the inhibition of iron accumulation and the increased expression of SLC7A11 and GPX4 ( Zhang et al, 2021 ). Previous study revealed that the restraint of iron availability through blocking CD71-mediated iron endocytosis damaged the differentiation and pathogenicity of TH 17 cells ( Li et al, 2021 ). We did not examine the changes of iron death-related factors such as SLC7A11, CD71, ACSL4 and GPX4.…”

Section: Discussionmentioning

confidence: 99%

Formononetin Attenuates Renal Tubular Injury and Mitochondrial Damage in Diabetic Nephropathy Partly via Regulating Sirt1/PGC-1α Pathway

et al. 2022

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Mitochondrial abnormality is one of the main factors of tubular injury in diabetic nephropathy (DN). Formononetin (FMN), a novel isoflavonoid isolated from Astragalus membranaceus, has diverse pharmacological activities. However, the beneficial effects of FMN on renal tubular impairment and mitochondrial dysfunction in DN have yet to be studied. In this study, we performed in vivo tests in Streptozotocin (STZ) -induced diabetic rats to explore the therapeutic effects of FMN on DN. We demonstrated that FMN could ameliorate albuminuria and renal histopathology. FMN attenuated renal tubular cells apoptosis, mitochondrial fragmentation and restored expression of mitochondrial dynamics-associated proteins, such as Drp1, Fis1 and Mfn2, as well as apoptosis-related proteins, such as Bax, Bcl-2 and cleaved-caspase-3. Moreover, FMN upregulated the protein expression of Sirt1 and PGC-1α in diabetic kidneys. In vitro studies further demonstrated that FMN could inhibit high glucose-induced apoptosis of HK-2 cells. FMN also reduced the production of mitochondrial superoxide and alleviated mitochondrial membrane potential (MMP) loss. Furthermore, FMN partially restored the protein expression of Drp1, Fis1 and Mfn2, Bax, Bcl-2, cleaved-caspase-3, Sirt1 and PGC-1α in HK-2 cells exposure to high glucose. In conclusion, FMN could attenuate renal tubular injury and mitochondrial damage in DN partly by regulating Sirt1/PGC-1α pathway.

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“…Given the breadth and conserved nature of pathways involving iron interacting proteins it follows that iron deprivation would likely have broad implications on cell biochemistry, health, and function with potential knock-on effects at the tissue or systemic levels. Our work explains why iron depletion potently suppresses T-cell responses in models of immunisation, infection, and autoimmunity 5,17,46–48 . We also propose that the iron deficiency-associated perturbations described here may in part be responsible for cellular dysfunction in other cell types and tissues during iron deficiency.…”

Section: Discussionmentioning

confidence: 75%

Iron deficiency causes aspartate-sensitive metabolic and proliferative dysfunction in CD8+ T cells

Teh,

Gudgeon,

Frost

et al. 2024

Preprint

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Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people, causing symptoms including anaemia and impaired immunity. Nevertheless, precisely how iron deprivation impacts immune cell function remains poorly characterised. We therefore interrogated how physiologically low iron availability affected activated CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation profoundly stalled proliferation without influencing cell viability, altered histone methylation status and disrupted mitochondrial membrane potential. Consistently, metabolism of glucose and glutamine in the TCA cycle was limited, indeed TCA cycle activity was partially reversed to a reductive trajectory. Previous studies have shown mitochondria-derived aspartate is crucial for proliferation of transformed cells. Surprisingly, we found aspartate was increased in stalled iron deficient CD8+ T-cells, but was not utilised cytosolically for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Conversely, exogenous aspartate, which directly accesses the cytosol, markedly rescued the clonal expansion of even severely iron-deficient CD8+ T-cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck impairing T-cells, which can be bypassed by resupplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.

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Iron deprivation restrains the differentiation and pathogenicity of T helper 17 cell

Cited by 13 publications

References 45 publications

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

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

Formononetin Attenuates Renal Tubular Injury and Mitochondrial Damage in Diabetic Nephropathy Partly via Regulating Sirt1/PGC-1α Pathway

Iron deficiency causes aspartate-sensitive metabolic and proliferative dysfunction in CD8+ T cells

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