T cell lipid peroxidation induces ferroptosis and prevents immunity to infection

By M. Matsushita, S. Freigang, C. Schneider, M. Conrad, G. Bornkamm, M. Kopf. Journal of Experimental Medicine, 2015

600 citations recorded by the source corpus.

Matsushita et al. investigated the role of the selenoenzyme glutathione peroxidae 4 (Gpx4) in T cell responses and found that loss of Gpx4 results in an intrinsic T cell developmental defect in the periphery, which leads to a failure to expand and protect from acute viral and parasitic infection.The defects were rescued with dietary supplementation of vitamin E. The Gp4−/− T cells accumulate membrane lipid peroxides and undergo cell death by ferroptosis.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/396a16d87a49342f2f9defd3e3a8f02bd1516d70

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Citations in the corpus

The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. (2017, neutral): “…prevents nuclear accumulation of DPP4 and then triggers membrane-associated DPP4-mediated lipid peroxidation, which finally results in ferroptosis. are sensitive to erastin (Friedmann Angeli et al., 2014; Jiang et al., 2015; Linkermann et al., 2014; Matsushita et al., 2015; Skouta et al., 2014).”
The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “15-LOX modulates the ferroptotic endurance in macrophages, similar to that in tumor cells,(115,117) while solely knocking out 12/15-LOX is insufficient to prevent lipid peroxidation in T cells.(11,118) Instead, 5LOX may be responsible for toxic lipid peroxidation in T cells lacking GPX4.”
Ferroptosis: Death by Lipid Peroxidation. (2016, background): “In addition, conditional deletion of Gpx4 in T cells in mice resulted in T cell ferroptosis, resulting in lack of an immune response to infection [46]; this suggests that Gpx4 is essential for a functional T-cell-mediated immune response.”
Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. (2017, neutral): “Vitamin E has been shown to protect cells against ferroptotic death in vitro [14;23;24] and in vivo in Gpx4 -/- knockout mice [41].”
Ferroptosis: mechanisms and links with diseases (2021, background): “However, both antigenspecific CD8 and CD4 T cells failed to expand and to protect from acute infections, and CD8 T cells had an intrinsic defect in maintaining homeostatic balance in the periphery,(190) which can be rescued with a high dosage of vitamin E.(190) Ferroptosis also plays a significant r”
The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, neutral): “Genetic depletion of GPX4 can trigger ferroptosis in an iron-, MEK-, and ROS-dependent manner in vitro or in vivo [23,24,31].”
Ferroptosis in infection, inflammation, and immunity (2021, background): “Third, the genetic depletion of Gpx4 or treatment with GPX4 inhibitors (e.g., RSL3, ML162, and ML210) induces lipid peroxidation and concomitantly ferroptotic cell death in T cells in vitro (Drijvers et al., 2021; Matsushita et al., 2015).”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “35,42 However, genetic deletion of Alox15 in Gpx4 knockout mice failed to avert ferroptosis in vivo, 8 and Alox12/15 failed to restore the viability of Gpx4 de ﬁ cient T cells, 79 suggesting the existence of alternative mechanisms in certain contexts of ferroptosis.”