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.
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.
Cell Death Differ. 2024 Nov;31(11):1519-1533. doi: 10.1038/s41418-024-01353-y. Epub 2024 Aug 8.
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.
调节性 T（Treg）细胞的存活和抑制功能依赖于各种细胞内代谢和生理过程。我们的研究表明，Vps34 通过调节细胞代谢活动，在维持 Treg 细胞稳态和功能方面发挥着关键作用。Vps34 在 Treg 细胞中的缺失会导致自发的致命性全身性自身免疫紊乱和多组织炎症损伤，同时伴随着 Treg 细胞数量的减少，特别是具有高度免疫抑制活性的效应 Treg 细胞。在机制上，缺乏 Vps34 的 Treg 细胞的存活率降低归因于内吞作用、细胞内囊泡运输和自噬体形成受损，这进一步导致线粒体呼吸增强和过量 ROS 产生。清除过量的 ROS 可以有效地挽救缺乏 Vps34 的 Treg 细胞的死亡。在功能上，在恶性黑色素瘤模型中，急性缺失 Vps34 会增强 T 细胞介导的抗肿瘤活性，从而增强抗肿瘤免疫。总的来说，我们的研究结果强调了 Vps34 在协调 Treg 细胞稳态和功能方面的关键作用，有助于建立免疫稳态和耐受。
