调节性 T (Treg) 细胞的生存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。 Treg 细胞中 Vps34 的破坏会导致自发性致命性系统性自身免疫性疾病和多组织炎症损伤，并伴有 Treg 细胞数量减少，特别是具有高度免疫抑制活性的 eTreg 细胞。从机制上讲，Vps34缺陷的Treg细胞的存活率低下归因于内吞作用、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ROS产生过多。去除过量的ROS可以有效挽救Vps34缺陷的Treg细胞的死亡。从功能上讲，已建立的 Treg 细胞内 Vps34 的急性缺失可通过增强 T 细胞介导的抗肿瘤活性来增强恶性黑色素瘤模型中的抗肿瘤免疫。总体而言，我们的结果强调了 Vps34 在协调 Treg 细胞稳态和建立免疫稳态和耐受性的功能中发挥的关键作用。© 2024。作者获得 ADMC Associazione Differenziamento e Morte Cellulare 的独家许可。

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.© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.