ArticleProceedings of the National Academy of Sciences of the United States of America2024
Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 13 citations in OpenAlex.
- Decade-long persistence of CD19 CAR T cells in B cell lymphomas.Nature medicine · 2026Trial
- Spatial and single-cell transcriptomics landscape of adenomyosis.Journal of advanced research · 2026Article
- Ferroptosis in T cells: mechanisms, biology and translational opportunities.Nature reviews. Immunology · 2026Review
- Paracrine iron activates HopxJournal of advanced research · 2026Article
- From Iron to Depression: The Crosstalk Between the Periphery and Brain.Neuroscience bulletin · 2026Review
- Iron overload in the tumor microenvironment induces CD8Nature communications · 2026Article
- Longitudinal clinical and preclinical studies identify hetrombopag as a potent chelator for systemic iron overload.HemaSphere · 2026Article
- Iron and metabolic rewiring in cancer.Oncogenesis · 2026Review
- Competitive Binding of UBA52 and HOPX Modulates β-catenin Stability in Colorectal Cancer in the Context of High-Iron Intake.International journal of biological sciences · 2026Article
- Bioinformatics analysis and qRT-PCR validation of iron metabolism-related genes in pediatric asthma.PloS one · 2026Article
- The role of hormonal and nutritional biomarkers in predicting immune checkpoint inhibitor efficacy: current limitations and future prospects.Frontiers in immunology · 2026Review
- Metal homeostasis as a therapeutic lever: advancing metalloimmunology to remodel the tumor microenvironment and enhance cancer immunotherapy.Theranostics · 2026Review
- Fueling Death: The Metabolic Control of Ferroptosis.Advances in experimental medicine and biology · 2026Review
- Iron as an immunometabolic signal in infection and inflammation.Frontiers in immunology · 2026Review
- Immune cells dying from ferroptosis: mechanisms and therapeutic opportunities.Cell death & disease · 2025Review
- Nuclear Receptor Subfamily 4 Group A Member 1 Exacerbates Cardiac Remodeling by Inhibiting Mitochondrial Function Through the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α/Nuclear Respiratory Factor 1/Transcription Factor A Mitochondrial Axis.Journal of the American Heart Association · 2025Article
- The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment.Scientific reports · 2025Article
- From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review).International journal of oncology · 2025Review
- Ferroptosis of T cell in inflammation and tumour immunity.Clinical and translational medicine · 2025Review
- Decoding iron deficiency in cancer: mechanisms, immune modulation, and therapeutic potential.Frontiers in nutrition · 2025Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.