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Vps34 sustains Treg cell survival and function via regulating intracellular redox homeostasis

Cell Death & Differentiation (2024)Cite this article

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Abstract

The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.

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Fig. 1: Vps34 plays a crucial role in maintaining Treg cell-mediated prevention of lethal autoimmune disease.
Fig. 2: Ablation of Vps34 in Treg cells disrupts immune homeostasis.
Fig. 3: Vps34 is critical for Treg cell survival.
Fig. 4: Vps34 is necessary for the transition of cTreg to eTreg.
Fig. 5: Vps34 mediates Treg cell autophagy capacity and endocytosis.
Fig. 6: Deletion of Vps34 impairs Treg cell redox homeostasis.
Fig. 7: Vps34 is critical for Treg cell-mediated immunosuppressive function.
Fig. 8: Schematic illustration of Vps34 controls redox homeostasis to orchestrate Treg cell survival and function.

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Data availability

The RNA-seq data were deposited in the Sequence Read Archive (SRA) repository at NCBI under the accession number PRJNA917486.

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Acknowledgements

Research reported in this publication was supported by the Natural Science Foundation of China (to MY, 82271754 and 82071737; to PF, 82301974; to QY, 32000615; to SW, 82101831); Guangdong Basic and Applied Basic Research Fund (to MY, 2024A1515010566; to QY, 2023A1515012582; to PF, 2022A1515110217); The China Postdoctoral Science Foundation (to PF, 2023M741377); The 111 Project (B16021).

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  1. These authors contributed equally: Peiran Feng, Quanli Yang, Liang Luo, Zerong Guan.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai, China

    Peiran Feng, Quanli Yang, Liang Luo, Zerong Guan, Jiamin Fu, Mingyue Zhao, Wanqing Meng & Meixiang Yang

  2. Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan, China

    Peiran Feng, Zhizhong Li, Guodong Sun & Meixiang Yang

  3. State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, China

    Peiran Feng, Liang Luo, Zerong Guan, Jiamin Fu, Mingyue Zhao, Wanqing Meng & Meixiang Yang

  4. International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, China

    Shuo Wan & Guang Wang

  5. The First Affiliated Hospital of Anhui Medical University and Institute for Clinical Immunology, Anhui Medical University, Hefei, Anhui, China

    Junming He & Zhongjun Dong

  6. Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application. Institute of Laboratory Animal Science, School of Medicine, Jinan University, Guangzhou, China

    Meixiang Yang

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Contributions

PF, QY, LL, and ZG performed experiments, analyzed data, and wrote the manuscript. JF, MZ, WM, SW, JH, ZL and GS assisted with the preparation of reagents, data analysis and manuscript preparation. G.W helped in revising the text and rebuttal. MY and ZD conceptualized the project, designed and supervised the research, and wrote the manuscript.

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Correspondence to Zhongjun Dong or Meixiang Yang.

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All animal studies were approved by the Animal Ethics Committee of Jinan University (IACUC-20211229-02). No human samples were used in this article.

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Feng, P., Yang, Q., Luo, L. et al. Vps34 sustains Treg cell survival and function via regulating intracellular redox homeostasis. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01353-y

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