Li Yuqian, Jiang Qian, Geng Xiaokun, Zhao Haiping
Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
Beijing Geriatric Medical Research Center, Beijing, 100053, China.
J Neuroimmune Pharmacol. 2025 Jan 16;20(1):8. doi: 10.1007/s11481-025-10169-7.
IL-2/IL-2R inhibition improved the prognosis of ischemic stroke by regulating T cells, while the respective contribution of T cells with high/medium/low-affinity IL-2 receptors remained unclear. Single-cell RNA sequencing data of ischemic brain tissue revealed that most of the high-affinity IL-2R would be expressed by CD8 + T cells, especially by a highly-proliferative subset. Interestingly, only the CD8 + T cells with high-affinity IL-2R infiltrated ischemic brain tissues, highly expressing 32 genes (including Cdc20, Cdca3/5, and Asns) and activating 7 signaling pathways (including the interferon-alpha response pathway, a key mediator in the proliferation, migration, and cytotoxicity of CD8 + T cells). Its interaction with endothelial cells and the ligand-receptor interaction analysis also suggested an augmented brain infiltration after cerebral ischemia. In IL-2Rα KO mice, who would have no high- or low-affinity IL-2R in CD8 + T cells, the RNA-seq, qPCR, immunofluorescence, and multiplex assays found that the expression of CD8b, CD122, CD132, and Vcam-1 was upregulated in the acute phase of cerebral ischemia, with decreasing H2-k1 positive cells and increasing Vcam-1 and CD8b positive cells in brain tissue. However, inflammation pathways in brain were inhibited and peripheral inflammatory cytokine levels were reduced, indicating that CD8 + T cells changed into an anti-inflammatory phenotype. The IL-2Rα KO mice after cerebral ischemia also performed better in behavioral tests and had more favorable results in diffusion tensor imaging, electrophysiology, and MBP testing. Our findings suggested that the CD8 + T cells with high-affinity IL-2R, as well as IL-2Rα, might be targeted to improve the clinical management of ischemic stroke.
白细胞介素-2/白细胞介素-2受体抑制通过调节T细胞改善了缺血性中风的预后，而高/中/低亲和力白细胞介素-2受体的T细胞各自的作用仍不清楚。缺血性脑组织的单细胞RNA测序数据显示，大多数高亲和力白细胞介素-2受体将由CD8 + T细胞表达，特别是由一个高度增殖的亚群表达。有趣的是，只有具有高亲和力白细胞介素-2受体的CD8 + T细胞浸润缺血性脑组织，高度表达32个基因（包括Cdc20、Cdca3/5和Asns）并激活7条信号通路（包括干扰素-α反应通路，这是CD8 + T细胞增殖、迁移和细胞毒性的关键介质）。其与内皮细胞的相互作用以及配体-受体相互作用分析也表明脑缺血后脑部浸润增加。在CD8 + T细胞中没有高亲和力或低亲和力白细胞介素-2受体的白细胞介素-2受体α敲除小鼠中，RNA测序、定量聚合酶链反应、免疫荧光和多重分析发现，在脑缺血急性期，CD8b、CD122、CD132和血管细胞黏附分子-1的表达上调，脑组织中H2-k1阳性细胞减少，血管细胞黏附分子-1和CD8b阳性细胞增加。然而，脑中的炎症通路受到抑制，外周炎性细胞因子水平降低，表明CD8 + T细胞转变为抗炎表型。脑缺血后的白细胞介素-2受体α敲除小鼠在行为测试中也表现更好，在扩散张量成像、电生理学和髓鞘碱性蛋白测试中也有更有利的结果。我们的研究结果表明，具有高亲和力白细胞介素-2受体的CD8 + T细胞以及白细胞介素-2受体α可能是改善缺血性中风临床治疗的靶点。
