{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T11:14:24Z","timestamp":1793186064326,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Nevertheless, exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T (T\n                    <jats:sub>EX<\/jats:sub>\n                    ) cells still preserve certain effector function, and maintaining a reservoir of exhausted cells is of vital importance for virus elimination and tumor eradiation. Despite considerable work interrogating the rejuvenation of T\n                    <jats:sub>EX<\/jats:sub>\n                    cells, mechanisms underpinning the clonal deletion of T\n                    <jats:sub>EX<\/jats:sub>\n                    cells remain largely unexplored over the past decade. In this study, we employed mouse models of LCMV infection to demonstrate that excessive accumulation of lipid peroxidation rendered virus-specific T\n                    <jats:sub>EX<\/jats:sub>\n                    cells to ferroptosis, which may correlate with enhanced mitochondria-derived oxidative stress and compromised activity of glutathione peroxidase 4 (GPX4). In addition, either incomplete or complete ablation of GPX4 resulted in exacerbated ferroptosis and aggravated shrunken population of virus-specific T\n                    <jats:sub>EX<\/jats:sub>\n                    cells. On the other hand, inhibiting ferroptosis via administration of a ferroptosis inhibitor or overexpression of GPX4 greatly rectified the cell loss of virus-specific T\n                    <jats:sub>EX<\/jats:sub>\n                    cells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific T\n                    <jats:sub>EX<\/jats:sub>\n                    cells and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific T\n                    <jats:sub>EX<\/jats:sub>\n                    cells.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2024.1490845","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T01:25:40Z","timestamp":1732497940000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8+ T cells"],"prefix":"10.3389","volume":"15","author":[{"given":"Qin","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuming","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri778","article-title":"Effector and memory T-cell differentiation: Implications for vaccine development","volume":"2","author":"Kaech","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3307","article-title":"Transcriptional control of effector and memory CD8 T cell differentiation","volume":"12","author":"Kaech","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318","article-title":"CD8 T cell exhaustion during chronic viral infection and cancer","volume":"37","author":"McLane","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0793-3","article-title":"Disturbed mitochondrial dynamics in CD8 TILs reinforce T cell exhaustion","volume":"21","author":"Yu","year":"2020","journal-title":"Nat Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/imr.2017.277.issue-1","article-title":"Dying to protect: cell death and the control of T-cell homeostasis","volume":"277","author":"Li","year":"2017","journal-title":"Immunol Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.2125367","article-title":"Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo","volume":"250","author":"Murphy","year":"1990","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290345","article-title":"The role of apoptosis in the development and function of T lymphocytes","volume":"15","author":"Zhang","year":"2005","journal-title":"Cell Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.04.002","article-title":"Cholesterol induces CD8 T cell exhaustion in the tumor microenvironment","volume":"30","author":"Ma","year":"2019","journal-title":"Cell Metab"},{"key":"B10","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1158\/2326-6066.CIR-17-0249","article-title":"Intratumoral CD8(+) T-cell apoptosis is a major component of T-cell dysfunction and impedes antitumor immunity","volume":"6","author":"Horton","year":"2018","journal-title":"Cancer Immunol Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.06.015","article-title":"Cell-intrinsic transforming growth factor-\u03b2 Signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo","volume":"31","author":"Tinoco","year":"2009","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.v3.1","article-title":"Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8(+) T cells","volume":"3","author":"Chen","year":"2022","journal-title":"MedComm"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11137","article-title":"Cell death: a review of the major forms of apoptosis, necrosis and autophagy","volume":"43","author":"D'Arcy","year":"2019","journal-title":"Cell Biol Int"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.04.024","article-title":"The coming decade of cell death research: five riddles","volume":"177","author":"Green","year":"2019","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01090-1","article-title":"The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4 T cells by preventing ferroptosis","volume":"23","author":"Wang","year":"2022","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1146\/annurev-cancerbio-030518-055844","article-title":"The hallmarks of ferroptosis","volume":"3","author":"Dixon","year":"2019","journal-title":"Annu Rev Canc Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140857","article-title":"T cell lipid peroxidation induces ferroptosis and prevents immunity to infection","volume":"212","author":"Matsushita","year":"2015","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.02.015","article-title":"CD36-mediated ferroptosis dampens intratumoral CD8 T cell effector function and impairs their antitumor ability","volume":"33","author":"Ma","year":"2021","journal-title":"Cell Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.05.003","article-title":"Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8 T cells in tumors","volume":"54","author":"Xu","year":"2021","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06503-1","article-title":"Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8 T cells","volume":"15","author":"Han","year":"2024","journal-title":"Cell Death Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.08.003","article-title":"PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8(+) T cell ferroptosis","volume":"57","author":"Ping","year":"2024","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01614-x","article-title":"Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8 T cell exhaustion","volume":"24","author":"Till\u00e9","year":"2023","journal-title":"Nat Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining 'T cell exhaustion'","volume":"19","author":"Blank","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00169","article-title":"The transcription factor TCF1 preserves the effector function of exhausted CD8 T cells during chronic viral infection","volume":"10","author":"Wang","year":"2019","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2007.08.025","article-title":"Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo","volume":"147","author":"McCausland","year":"2008","journal-title":"J Virol Methods"},{"key":"B32","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/s41590-019-0403-4","article-title":"Single-cell RNA-seq reveals TOX as a key regulator of CD8 T cell persistence in chronic infection","volume":"20","author":"Yao","year":"2019","journal-title":"Nat Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw9872","article-title":"Cysteine depletion induces pancreatic tumor ferroptosis in mice","volume":"368","author":"Badgley","year":"2020","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02523","article-title":"Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis","volume":"3","author":"Dixon","year":"2014","journal-title":"Elife"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/82_2016_508","article-title":"Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis","volume":"403","author":"Imai","year":"2017","journal-title":"Curr Top Microbiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00834-9","article-title":"Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion","volume":"22","author":"Scharping","year":"2021","journal-title":"Nat Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature19317","article-title":"Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection","volume":"537","author":"He","year":"2016","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330","article-title":"Defining CD8 T cells that provide the proliferative burst after PD-1 therapy","volume":"537","author":"Im","year":"2016","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","article-title":"Intratumoral Tcf1+ PD-1+ CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy","volume":"50","author":"Siddiqui","year":"2019","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.020","article-title":"The primordial differentiation of tumor-specific memory CD8+T cells as bona fide responders to PD-1\/PD-L1 blockade in draining lymph nodes","volume":"185","author":"Huang","year":"2022","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adh1306","article-title":"BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1","volume":"8","author":"Sun","year":"2023","journal-title":"Sci Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801497105","article-title":"Selective expansion of a subset of exhausted CD8 T cells by \u03b1PD-L1 blockade","volume":"105","author":"Blackburn","year":"2008","journal-title":"P Natl Acad Sci USA"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229620","article-title":"Progenitor and terminal subsets of CD8 T cells cooperate to contain chronic viral infection","volume":"338","author":"Paley","year":"2012","journal-title":"Sci (New York NY)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.002","article-title":"Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ Stem-like CD8 T cells during chronic infection","volume":"51","author":"Hudson","year":"2019","journal-title":"Immunity"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.014","article-title":"Developmental relationships of four exhausted CD8 T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms","volume":"52","author":"Beltra","year":"2020","journal-title":"Immunity"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1490845\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T01:25:41Z","timestamp":1732497941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1490845\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,25]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2024.1490845"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1490845","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,25]]},"article-number":"1490845"}}