Department of Allergy, The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, 230032, China.
Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, 230032, China.
Adv Sci (Weinh). 2024 Jun;11(21):e2309315. doi: 10.1002/advs.202309315. Epub 2024 Mar 27.
Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34/CD122) is generated, deleting Vps34 during and after NK-cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL-15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL-15. In mice lacking Vps34 at the terminal stage of NK-cell development (Vps34/Ncr1), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34-mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34-mediated autophagy can delay NK cell senescence.
Vps34 是唯一的 III 类磷酸肌醇 3-激酶家族成员，具有囊泡运输和自噬的双重功能。其在自然杀伤 (NK) 细胞中的作用尚不清楚。在这项研究中，生成了一种没有 Vps34（Vps34/CD122）的模型，在 NK 细胞承诺期间和之后删除 Vps34。这些小鼠的 NK 细胞计数减少了近 90%，分化受损。一项机制研究表明，缺乏 Vps34 会破坏 IL-15 受体亚基 alpha CD122 向细胞膜的运输，导致 NK 细胞对 IL-15 的反应性降低。在 NK 细胞发育终末阶段（Vps34/Ncr1）缺乏 Vps34 的小鼠中，NK 细胞在衰老过程中逐渐减少。这种表型与自噬缺陷和活性氧物质 (ROS) 诱导的应激有关。因此，终末分化的缺乏 Vps34 的 NK 细胞表现出加速衰老的表型，而抗氧化剂的应用通过中和 ROS 有效地逆转了由 Vps34 删除引起的衰老。总之，这项研究揭示了 Vps34 在 NK 细胞中的双重和独特活性。Vps34 介导的囊泡运输对于 NK 细胞承诺期间 CD122 的膜转运至关重要，而 Vps34 介导的自噬可以延缓 NK 细胞衰老。
