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T cell lipid peroxidation induces ferroptosis and prevents immunity to infection
Open accessAbstract
The selenoenzyme glutathione peroxidase 4 (Gpx4) is a major scavenger of phospholipid hydroperoxides. Although Gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. Here, we investigated the importance of Gpx4 for physiological T cell responses by using T cell–specific Gpx4-deficient mice. Our results revealed that, despite normal thymic T cell development, CD8+ T cells from TΔGpx4/ΔGpx4 mice had an intrinsic defect in maintaining homeostatic balance in the periphery. Moreover, both antigen-specific CD8+ and CD4+ T cells lacking Gpx4 failed to expand and to protect from acute lymphocytic choriomeningitis virus and Leishmania major parasite infections, which were rescued with diet supplementation of high dosage of vitamin E. Notably, depletion of the Gpx4 gene in the memory phase of viral infection did not affect T cell recall responses upon secondary infection. Ex vivo, Gpx4-deficient T cells rapidly accumulated membrane lipid peroxides and concomitantly underwent cell death driven by ferroptosis but not necroptosis. These studies unveil an essential role of Gpx4 for T cell immunity.
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“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [567]
In the citing paper
“GPX4 is essential for the survival and expansion of recently activated T cells, indicating the importance of preventing lipid peroxidation and of iron dysregulation resulting in ferroptosis, in T cell proliferation (Matsushita et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Matsushita et al., 2015
In the citing paper
“GPX4 is essential for the survival and expansion of recently activated T cells, indicating the importance of preventing lipid peroxidation and of iron dysregulation resulting in ferroptosis, in T cell proliferation (Matsushita et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Matsushita et al., 2015
In the citing paper
“Gpx4 exerts important effects on the immune system as it is crucial for the survival of CD8+ T cells and for the expansion of both CD4+ and CD8+ T cells upon T cell receptor triggering in response to infection by preventing membrane lipid peroxidation and ferroptosis”
From Iron in immune cell function and host defense (2021) · cites this paper as [112]
In the citing paper
“and high levels of reactive oxygen species in T cells impair cytotoxicity, perhaps mediated by T cell lipid peroxidation, resulting in failure to control viruses (Henson et al. 2014; Matsushita et al. 2015).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Matsushita et al. 2015
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Cites
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“Indeed, RAS–RAF–MEK signaling has been shown to be required for erastin-induced ferroptosis of tumor cells (Yagoda et al., 2007).”
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Items 201–300 of 677
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BackgroundA white paper on Phospholipid Hydroperoxide Glutathione Peroxidase (GPx4) forty years later
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“RIP1 Increased thymocyte apoptosis in response to Fas, TNF (KO) (19) RelB Increased thymocyte apoptosis in response to anti-CD3 (KO) (14) Ubc13 Regulates Tak1 and NF-kB signaling in thymocytes (Lck-Cre cKO) (16) Gpx4 Increased ferroptosis in splenic T cells to superantigen or anti-CD3 (CD4-Cre) (51)”
BackgroundEscherichia coli induced ferroptosis in red blood cells of grass carp (Ctenopharyngodon idella)
Yang, M., Lu, Z., Li, F., Shi, F., Zhan, F., Zhao, L., Li, Y., Li, J., Lin, L., & Qin, Z. (2020) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2020.09.036 · Cited by 72
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Ferroptosis and its role in cardiomyopathy
Li, D., Pi, W., Sun, Z., Liu, X., & Jiang, J. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113279 · Cited by 72
Ferroptosis in ulcerative colitis: Potential mechanisms and promising therapeutic targets
Long, D., Mao, C., Huang, Y., Xu, Y., & Zhu, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116722 · Cited by 81
Ferroptosis and its Role in Gastric Cancer
Gu, R., Xia, Y., Li, P., Zou, D., Lu, K., Ren, L., Zhang, H., & Sun, Z. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.860344 · Cited by 75
“These signals produced during cell death allow the recruitment and activation of immune cells, such as macrophages, regulatory T cell, and neutrophils (Matsushita et al., 2015; Klöditz and Fadeel, 2019; Li et al., 2019), which regulate the growth and expansion of other cancer cells.”
Backgroundp53: A double-edged sword in tumor ferroptosis
Ji, H., Wang, W., Li, X., Han, X., Zhang, X., Wang, J., Liu, C., Huang, L., & Gao, W. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.106013 · Cited by 71
The Potential Role of Ferroptosis in Alzheimer’s Disease
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“Besides, Kopf et al. also suggested a synergistic int-errelationship between GPX4 and vitamin E to inhibit lipid peroxidation-mediated ferroptosis in T-cell immunity, in both in vivo and in vitro models [70].”
Vitamin E research: Past, now and future
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Ferroptosis: a promising target for cancer immunotherapy.
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“…therapy when drug resistance to immunotherapy occurs, especially for cancer cells with dedif-ferentiated phenotypes. distribution and metabolic activity of APCs and MDSCs in juxtaposition to T cells could provide vital predictive insights for ferroptosis therapeutic trajectories [41, 42, 56].”
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Prospects for ferroptosis therapies in cancer
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“Moreover, conditional Gpx4 deletion leads to immune defects in T cells, B cells and innate lymphoid cells under steady-state conditions 71,72 .”
Iron, lipid peroxidation, and ferroptosis play pathogenic roles in atherosclerosis
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Targetting ferroptosis for blood cell-related diseases
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“org 2 response rates to infection (15).”
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“In contrast to hematopoietic progenitor cells, hematopoietic stem cells are more susceptible to ferroptosis, possibly due to their lower protein synthesis rate [82].”
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“Furthermore, pertinent studies have demonstrated that GPX4 can inhibit ferroptosis in T cells, thus preserving their immune functionality [23].”
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p21 can be a barrier to ferroptosis independent of p53
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“Excessive ferroptosis has also been shown to be a key effector of cardiomyopathy [8], renal damage and failure [9, 10] and can also potentially mediate the loss of immunity against infection [11].”
BackgroundFerroptosis in tumor immunity and therapy
Gong, C., Ji, Q., Wu, M., Tu, Z., Lei, K., Luo, M., Liu, J., Lin, L., Li, K., Li, J., et al. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17529 · Cited by 56
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Cell‐type‐specific insights into iron regulatory processes
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“Depletion of this enzyme in hematopoietic cells leads to impaired erythroid maturation (Figure 5),(81) whereas its T cell specific knock-out hampers activation of both CD4 and CD8 lymphocytes in response to infection (Figure 3).(82) High expression of ferritin in T cells,(83) the observation that T and B cells may acq…”
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“GPX4 deficiency blocked T-cell survival and B-cell development (Matsushita et al., 2015; Muri et al., 2019).”
BackgroundCell death in skin function, inflammation, and disease
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Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications
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“And lots of investigations have shown that GPX4 is related to the development process of human diseases (Friedmann Angeli et al., 2014; Matsushita et al., 2015).”
BackgroundFerroptosis: A Critical Moderator in the Life Cycle of Immune Cells
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“12,13 16 Many genes have been validated to promote ferroptosis in tumor cells, such as FBXW7, 17 G6PD, 12 and TP53, 18,19 while CISD2, 20 GPX4, 21 – 23 and SLC7A11 24,25 serve as suppressors to prevent ferroptosis.”
Maekawa, T., Kashkar, H., & Coll, N. S. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01060-6 · Cited by 53
“In line with this notion, T cell lipid peroxidation and ferroptosis were shown to prevent immunity against Choriomeningitis virus [110].”
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Ferroptosis-mediated immune responses in cancer
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“In addition to Fer-1 treatment, dietary supplementation of vitamin E, a powerful antioxidant that has been previously shown to ameliorate ferroptosis in T cells (53), showed a trend in ameliorating the decline of NIX-deficient P14 T cells (fig.”
BackgroundYan, J., Zeng, Y., Guan, Z., Li, Z., Luo, S., Niu, J., Zhao, J., Gong, H., Huang, T., Li, Z., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114636 · Cited by 54
T Cells and Regulated Cell Death
Spetz, J. K. E., Presser, A. G., & Sarosiek, K. A. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.07.004 · Cited by 55
Selenoproteins as regulators of T cell proliferation, differentiation, and metabolism
Ma, C., & Hoffmann, P. R. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.11.006 · Cited by 52
Zhang, Q., Gong, H.-B., Jiang, M.-Y., Jin, F., Wang, G., Yan, C., Luo, X., Sun, W., Ouyang, S., Wu, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55929-4 · Cited by 51
“Initially, we investigated vitamin E as a pharmacological inhibitor of phospholipid peroxidation, inspired by previous studies 44 – 48 .”
Targeting of regulated necrosis in kidney disease
Martín‐Sánchez, D., Poveda, J., Fontecha‐Barriuso, M., Ruiz‐Andrés, O., Sánchez-Niño, M. D., Ruiz‐Ortega, M., Ortíz, A., & Sanz, A. B. (2017) · Nefrología · doi:10.1016/j.nefro.2017.04.004 · Cited by 52
Ferroptosis: The Greasy Side of Cell Death
Angeli, J. P. F., Miyamoto, S., & Schulze, A. (2019) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00349 · Cited by 50
Ferroptosis: Mechanism and connections with cutaneous diseases
Liu, L., Lian, N., Shi, L., Hao, Z., & Chen, K. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1079548 · Cited by 52
“CD8 T cells of the knockout mice were intrinsically defective in balancing homeostasis in the peripheral environment, implicating GPX4 is required for T cellregulated immune responses (Matsushita et al., 2015).”
BackgroundGPX4: old lessons, new features
da Silva, T. N. X., Angeli, J. P. F., & Ingold, I. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220682 · Cited by 52
Buday, K., & Conrad, M. (2020) · Biological Chemistry · doi:10.1515/hsz-2020-0286 · Cited by 48
“2014), CD8+ T cell mediated immunity (Matsushita et al. 2015), hematopoiesis (Altamura et al.”
BackgroundSelf-citationCD8+ T cells PUF(A)ing the flames of cancer ferroptotic cell death
Angeli, J. P. F., da Silva, T. N. X., & Schilling, B. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.03.003 · Cited by 48
Srivastava, N., Hu, H., Peterson, O. J., Vomund, A. N., Stremska, M. E., Zaman, M., Giri, S., Li, T., Lichti, C. F., Zakharov, P. N., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.04.017 · Cited by 50
Selenium-Dependent Glutathione Peroxidases During Tumor Development
Kipp, A. P. (2017) · Advances in cancer research · doi:10.1016/bs.acr.2017.07.004 · Cited by 47
“In addition, aGPx4 knockout reduced T cell survival, which can be prevented by inhibiting MEK1/2 and subsequent ERK1/2 activation, indicating that deregulated ERK activation is caused by enhanced lipid peroxidation (Matsushita et al., 2015).”
BackgroundThe Role of Ferroptosis in Adverse Left Ventricular Remodeling Following Acute Myocardial Infarction
Komai, K., Kawasaki, N. K., Higa, J. K., & Matsui, T. (2022) · Cells · doi:10.3390/cells11091399 · Cited by 48
“T cell survival and proliferation are also suggested to be regulated by ferroptosis, as a GPX4-deficient T cell model showed that GPX4 was required for CD4+ T cell and CD8+ T cell proliferation during infection [103].”
BackgroundRuiz‐de‐Angulo, A., Bilbao‐Asensio, M., Cronin, J., Evans, S. J., Clift, M. J. D., Llop, J., Feiner, I. V. J., Beadman, R., Zamacola, K., & Rivas, J. C. M. (2020) · iScience · doi:10.1016/j.isci.2020.101499 · Cited by 45
Ozone Pollution, Oxidative Stress, Regulatory T Cells and Antioxidants
Rivas-Arancibia, S., Hernández-Orozco, E., Rodrı́guez-Martı́nez, E., Valdés‐Fuentes, M., Cornejo-Trejo, V., Pérez-Pacheco, N., Dorado-Martı́nez, C., Zequeida-Carmona, D., & Caleti, I. E. (2022) · Antioxidants · doi:10.3390/antiox11081553 · Cited by 45
Impaired iron recycling from erythrocytes is an early hallmark of aging
Slusarczyk, P., Mandal, P. K., Zurawska, G., Niklewicz, M., Chouhan, K., Mahadeva, R., Jończy, A., Macias, M., Szybińska, A., Cybulska, M., et al. (2023) · eLife · doi:10.7554/elife.79196 · Cited by 40
“…cell death was mainly described in genetic models, for example with disturbed detoxification of lipid peroxides due to conditional loss of Gpx4 ( Friedmann Angeli et al., 2014 ; Matsushita et al., 2015 ) or in various pathologies ( Park et al., 2019 ; Wang et al., 2019 ; Yan et al., 2021 ).”
Deciphering the potential roles of ferroptosis in regulating tumor immunity and tumor immunotherapy
Gu, X., Liu, Y., Dai, X., Yang, Y., & Zhang, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1137107 · Cited by 43
Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection
Xia, H., Zhang, Z., & You, F. (2021) · Viruses · doi:10.3390/v13122383 · Cited by 45
“For example, ferroptosis in T cells suppressed T cell expansion, and prevented viral clearance [63].”
BackgroundFerroptosis, novel therapeutics in asthma
Lv, X., Dong, M., Tang, W., Qin, J., Wang, W., Li, M., Teng, F., Yi, L., Dong, J., & Wei, Y. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113516 · Cited by 43
Wang, X., Chen, Y., Xiang, Y., Cheng, L., He, Z., Xin, Y., Huang, S., Meng, F., Zhang, P., & Luo, L. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05462-9 · Cited by 46
“1e), suggesting the characteristic of lipid ROS-induced ferroptosis [19].”
BackgroundChen, S., Fan, J., Xie, P., Ahn, J., Fernandez, M., Billingham, L. K., Miska, J. M., Wu, J. D., Wainwright, D. A., Fang, D., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci170071 · Cited by 43
“Activated T cells without GPX4 accumulate cellular lipid peroxides and undergo ferroptosis (21, 39, 40), while ferroptotic oxidative signals are produced primarily by iron-mediated Fenton reaction or enzymatic reaction via lipoxygenases or the dysregulated GSH antioxidant system (41, 42).”
BackgroundInfluentialLi, Z., Zhang, Y. Z., Ji, M., Wu, C., Zhang, Y., & Ji, S.-L. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116777 · Cited by 42
Impact of Micronutrients on the Immune Response of Animals
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Lipid peroxidation of immune cells in cancer
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Zeng, C., Nie, D., Wang, X., Zhong, S., Zeng, X., Liu, X., Qiu, K., Peng, X., Zhang, W., Chen, S., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02162-0 · Cited by 42
“As a pivotal regulator of ferroptosis, GPX4 plays a crucial role in maintaining cellular integrity [37–39], as well as in hematopoietic system [40, 41].”
BackgroundReprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance
Bhowmick, S., Banerjee, S., Shridhar, V., & Mondal, S. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02337-3 · Cited by 46
“Additionally, Bi-allelic deletion of GPX4 significantly reduced CD8 + T-cell numbers in the periphery while keeping CD4 + T-cells and Tregs intact, revealing differential need and sensitivity of fer-roptosis within different T-cell subsets [141].”
Ferroptosis Regulation by Nutrient Signalling
Qi, Y., Zhang, X., Wu, Z., Tian, M., Chen, F., Guan, W., & Zhang, S. (2021) · Nutrition Research Reviews · doi:10.1017/s0954422421000226 · Cited by 42
“Dietary supplementation with vitamin E restores the dysfunction of T cells induced by Gpx4 deficiency(57).”
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Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges
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“Conditional deletion of Gpx4 induces ferroptosis in T cells by lipid peroxidation in mice (Matsushita et al., 2015).”
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Targeting ferroptosis in autoimmune diseases: Mechanisms and therapeutic prospects
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Ma, X., Yan, W., & He, N. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12666 · Cited by 39
The Emerging Role of Heat Shock Factor 1 (HSF1) and Heat Shock Proteins (HSPs) in Ferroptosis
Aolymat, I., Hatmal, M. M., & Olaimat, A. N. (2023) · Pathophysiology · doi:10.3390/pathophysiology30010007 · Cited by 39
Plaza‐Sirvent, C., Schuster, M., Neumann, Y., Heise, U., Pils, M. C., Schulze‐Osthoff, K., & Schmitz, I. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.022 · Cited by 38
Redox Epiphospholipidome in Programmed Cell Death Signaling: Catalytic Mechanisms and Regulation
Kagan, V. E., Tyurina, Y. Y., Vlasova, I. I., Kapralov, A. A., Amoscato, A. A., Anthonymuthu, T. S., Tyurin, V. A., Shrivastava, I. H., Cinemre, F. B. S., Lamade, A. M., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.628079 · Cited by 39
Metadata
- Authors
- Matsushita, M., Freigang, S., Schneider, C., Conrad, M., Bornkamm, G. W., & Kopf, M.
- Affiliations
- ETH Zurich (CH)
- Helmholtz Munich (DE)
- Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland 1
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2015-03-30
- Volume
- 212
- Issue
- 4
- Pages
- 555-568
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4387287
- OpenAlex
- W2065934830
- Cited by
- 672
- References
- 57
- Citations by year
- 2026: 65 · 2025: 77 · 2024: 90 · 2023: 90 · 2022: 95 · 2021: 92 · 2020: 56 · 2019: 28 · 2018: 25 · 2017: 22 · 2016: 24 · 2015: 8
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by-nc-sa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc-sa)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- ETH Zürich Research Collection
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (141175, 310030B_141175/1)
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- GPX4, ferroptosis, lipid peroxidation, T cell immunity, CD8+ T cells, CD4+ T cells, phospholipid hydroperoxides, vitamin E, lymphocytic choriomeningitis virus, Leishmania major, antiviral immunity, antiparasitic immunity, T cell homeostasis, T cell-specific knockout mice
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Cell Membrane, Glutathione Peroxidase, Immunologic Memory, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Thymus Gland, Vitamin E, Vitamins, Lipid Peroxidation, CD4-Positive T-Lymphocytes, Leishmaniasis, Cutaneous, Cell Death, Leishmania major, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice
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