title: T cell lipid peroxidation induces ferroptosis and prevents immunity to infection.
abstract: 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 T(ΔGpx4/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.
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Mai
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Helmholtz Zentrum München, Institute of Developmental Genetics, 85764 Neuherberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: Helmholtz Zentrum München, Institute of Clinical Molecular Biology and Tumor Genetics, 81377 Munich, Germany.
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Science, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland Manfred.Kopf@ethz.ch.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology; D005979:Glutathione Peroxidase / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015227:Lipid Peroxidation / Q000235:genetics / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014810:Vitamin E / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
chemical_list: D014815:Vitamins; D014810:Vitamin E; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
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