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ORIGINAL RESEARCH article
Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1490845
Ferroptosis exacerbates the clonal deletion of virus-specific exhausted CD8 + T cells
Provisionally accepted- 1 Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
- 2 Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- 3 Institute of Immunology, Third Military Medical University, Chongqing, China
- 4 Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China
- 5 School of Life Sciences, Chongqing University, Chongqing, China
During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8 + T cells. Nevertheless, exhausted CD8 + T (TEX) 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 TEX cells, mechanisms underpinning the clonal deletion of TEX 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 TEX 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 TEX 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 TEX cells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific TEX cells, and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific TEX cells.
Keywords: ferroptosis, exhausted CD8 + T cells, Clonal Deletion, t cell exhaustion, lcmv, Chronic viral infection, GPx4, Persistence
Received: 03 Sep 2024; Accepted: 30 Oct 2024.
Copyright: © 2024 Tian, Chen, Lu, Zheng, Zhai, Yang, Zhao, Hao, Yang, Ye and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qin Tian, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
Cheng Chen, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
Yanping Yang, School of Life Sciences, Chongqing University, Chongqing, 405200, China
Ziyao Zhao, Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China
Jiangtao Hao, Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China
Lilin Ye, Institute of Immunology, Third Military Medical University, Chongqing, China
Yifei Wang, Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China
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