Selenium-GPX4 axis protects follicular helper T cells from ferroptosis

Yin Yao^#^{1

2

3}, Zhian Chen^#^{2

3}, Hao Zhang^#^{4

5}, Cailing Chen¹, Ming Zeng¹, Joseph Yunis^{2

3}, Yunbo Wei⁴, Yanmin Wan^{6

7}, Naiqi Wang², Mingzhe Zhou⁸, Chao Qiu⁹, Qunxiong Zeng¹⁰, Hong Sheng Ong³, Hao Wang³, Fadzai Victor Makota³, Yang Yang², Zhaohui Yang⁵, Nan Wang¹, Jun Deng^{5

10}, Chao Shen¹¹, Yan Xia⁵, Lin Yuan⁵, Zhaoqin Lian¹, Yike Deng¹, Cuilian Guo¹, Ao Huang¹, Pengcheng Zhou³, Haibo Shi¹², Weitian Zhang¹², Hongliang Yi¹², Dongmei Li¹³, Ming Xia¹⁴, Jing Fu¹⁵, Ning Wu¹⁶, Judy B de Haan¹⁷, Nan Shen¹⁰, Wenhong Zhang⁶, Zheng Liu¹⁸, Di Yu^{19

20

21

22

23}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
⁴ Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.
⁵ Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Minda Hospital of Hubei Minzu University, Enshi, China.
⁶ Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁸ State Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Diagnostics Co., Ltd., Nanjing, China.
⁹ Minhang Hospital and Huashan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
¹⁰ China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹¹ State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
¹² Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
¹³ Department of Otolaryngology, Qilu Children's Hospital of Shandong University, Jinan, China.
¹⁴ Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory for Hearing Reconstruction of Shandong Province, Jinan, China.
¹⁵ Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Australia.
¹⁶ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁷ Baker Heart and Diabetes Institute, Monash University, Melbourne, Australia.
¹⁸ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. zhengliuent@hotmail.com.
¹⁹ The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia. di.yu@uq.edu.au.
²⁰ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia. di.yu@uq.edu.au.
²¹ Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. di.yu@uq.edu.au.
²² Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Minda Hospital of Hubei Minzu University, Enshi, China. di.yu@uq.edu.au.
²³ China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. di.yu@uq.edu.au.

^# Contributed equally.

PMID: 34413521
DOI: 10.1038/s41590-021-00996-0

Selenium-GPX4 axis protects follicular helper T cells from ferroptosis

Yin Yao et al. Nat Immunol. 2021 Sep.

. 2021 Sep;22(9):1127-1139.

doi: 10.1038/s41590-021-00996-0. Epub 2021 Aug 19.

Authors

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
⁴ Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.
⁵ Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Minda Hospital of Hubei Minzu University, Enshi, China.
⁶ Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁸ State Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Diagnostics Co., Ltd., Nanjing, China.
⁹ Minhang Hospital and Huashan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
¹⁰ China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹¹ State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
¹² Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
¹³ Department of Otolaryngology, Qilu Children's Hospital of Shandong University, Jinan, China.
¹⁴ Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Key Laboratory for Hearing Reconstruction of Shandong Province, Jinan, China.
¹⁵ Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Australia.
¹⁶ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁷ Baker Heart and Diabetes Institute, Monash University, Melbourne, Australia.
¹⁸ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. zhengliuent@hotmail.com.
¹⁹ The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Australia. di.yu@uq.edu.au.
²⁰ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia. di.yu@uq.edu.au.
²¹ Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China. di.yu@uq.edu.au.
²² Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases, Minda Hospital of Hubei Minzu University, Enshi, China. di.yu@uq.edu.au.
²³ China-Australia Centre for Personalised Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. di.yu@uq.edu.au.

^# Contributed equally.

PMID: 34413521
DOI: 10.1038/s41590-021-00996-0

Erratum in

Author Correction: Selenium-GPX4 axis protects follicular helper T cells from ferroptosis.
Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, Wei Y, Wan Y, Wang N, Zhou M, Qiu C, Zeng Q, Ong HS, Wang H, Makota FV, Yang Y, Yang Z, Wang N, Deng J, Shen C, Xia Y, Yuan L, Lian Z, Deng Y, Guo C, Huang A, Zhou P, Shi H, Zhang W, Yi H, Li D, Xia M, Fu J, Wu N, de Haan JB, Shen N, Zhang W, Liu Z, Yu D. Yao Y, et al. Nat Immunol. 2021 Dec;22(12):1599. doi: 10.1038/s41590-021-01063-4. Nat Immunol. 2021. PMID: 34608307 No abstract available.
Author Correction: Selenium-GPX4 axis protects follicular helper T cells from ferroptosis.
Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, Wei Y, Wan Y, Wang N, Zhou M, Qiu C, Zeng Q, Ong HS, Wang H, Makota FV, Yang Y, Yang Z, Wang N, Deng J, Shen C, Xia Y, Yuan L, Lian Z, Deng Y, Guo C, Huang A, Zhou P, Shi H, Zhang W, Yi H, Li D, Xia M, Fu J, Wu N, de Haan JB, Shen N, Zhang W, Liu Z, Yu D. Yao Y, et al. Nat Immunol. 2024 Sep;25(9):1764. doi: 10.1038/s41590-024-01949-z. Nat Immunol. 2024. PMID: 39117868 No abstract available.

Abstract

Follicular helper T (T_FH) cells are a specialized subset of CD4⁺ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of T_FH cell survival remains unclear. Here we report that T_FH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T_FH cell survival. The deletion of GPX4 in T cells selectively abrogated T_FH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T_FH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating T_FH homeostasis, which can be targeted to enhance T_FH cell function in infection and following vaccination.

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Comment in

Selenium saves ferroptotic T_FH cells to fortify the germinal center.
Linterman MA, Denton AE. Linterman MA, et al. Nat Immunol. 2021 Sep;22(9):1074-1076. doi: 10.1038/s41590-021-01007-y. Nat Immunol. 2021. PMID: 34413522 No abstract available.

References

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1. Vinuesa, C. G., Linterman, M. A., Yu, D. & MacLennan, I. C. Follicular helper T cells. Ann. Rev. Immunol. https://doi.org/10.1146/annurev-immunol-041015-055605 (2016).
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1. He, J. et al. Low-dose interleukin-2 treatment selectively modulates CD4(⁺) T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22, 991–993 (2016). - PubMed - DOI

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Selenium-GPX4 axis protects follicular helper T cells from ferroptosis

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Selenium-GPX4 axis protects follicular helper T cells from ferroptosis

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