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RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3- and FADD-mediated cell death

Cellular & Molecular Immunology volume 21, pages 80–90 (2024)Cite this article

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Abstract

Regulatory T (Treg) cells play an essential role in maintaining immune balance across various physiological and pathological conditions. However, the mechanisms underlying Treg homeostasis remain incompletely understood. Here, we report that RIPK1 is crucial for Treg cell survival and homeostasis. We generated mice with Treg cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death. Unlike conventional T cells, Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis. However, simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways. Thus, our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis, thereby providing novel insights into the mechanisms of Treg cell homeostasis.

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Acknowledgements

This work was supported by the following grants: National Key Research and Development Program of China (2021YFA1301402), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), National Key Research and Development Program of China (2021YFE0200900; 2022YFA0807300), National Natural Science Foundation of China (82101833, 82073901), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2021-2023)-0103], Top-level Clinical Discipline Project of Shanghai Pudong District (grant/award number: PWYgf 2021-01), and Training Plan for Discipline Leaders of Shanghai Pudong New Area Health Commission (grant/award number: PWRd2020-09).

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Author notes

  1. These authors contributed equally: Xiaoxue Deng, Lingxia Wang, Yunze Zhai.

Authors and Affiliations

  1. State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Xiaoxue Deng, Yunze Zhai, Qiuyue Liu, Fengxue Du, Jiazi Ren, Yunli Shen, Zuoren Yu & Haikun Wang

  2. CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China

    Xiaoxue Deng, Yunze Zhai, Yu Zhang, Wenxing Zhao, Tingtao Wu, Pei Hao & Haikun Wang

  3. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Lingxia Wang & Haibing Zhang

  4. The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Yiwen Tao & Yuejuan Zheng

  5. Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200433, China

    Jie Deng & Yongbing Cao

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  1. Xiaoxue Deng
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Contributions

HZ and HW conceived and supervised the research; XD, LW, YZ, ZY, YC, YS, YZ, HZ and HW contributed to the project design and discussions; XD, LW and YZ conducted the experiments; QL, YZ, WZ, YT, TW and JD helped with the mixed bone marrow chimera experiments and some phenotype analysis; FD and JR assisted with mouse models; PH did the bioinformatics analysis; XD, LW, YZ, ZY, YZ, HZ and HW wrote and edited the manuscript.

Corresponding authors

Correspondence to Yuejuan Zheng, Haibing Zhang or Haikun Wang.

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The authors declare no competing interests.

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Deng, X., Wang, L., Zhai, Y. et al. RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3- and FADD-mediated cell death. Cell Mol Immunol 21, 80–90 (2024). https://doi.org/10.1038/s41423-023-01113-x

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