Parkinson’s disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.

帕金森病 (PD) 是一种多方面的疾病，其特征是黑质纹状体多巴胺能神经元变性，导致运动和非运动功能障碍。路易体中 α-突触核蛋白 (αSYN) 的积累是 PD 的一个关键病理特征。尽管帕金森病的确切病因尚不清楚，但越来越多的证据表明，T 细胞的大脑浸润在疾病的发病机制中发挥着关键作用，导致神经炎症和多巴胺能神经变性。在这里，我们使用了大脑注入聚集 αSYN 的小鼠模型，该模型概括了 PD 患者中出现的运动和非运动功能障碍。我们发现，αSYN 诱导的小鼠运动功能障碍伴随着大脑中 Th17 (IL17+ CD4+) 细胞数量的增加，但不是 CD8+ T 细胞的数量增加。为了评估 T 细胞反应的调节是否可以挽救 αSYN 诱导的损伤，我们长期用选择性 T 细胞共刺激调节剂阿巴西普（8 mg/kg，皮下注射，每周 3 次）治疗动物。我们发现，阿巴西普治疗可减少 αSYN 输注小鼠大脑中的 Th1 (IFNƔ+ CD4+) 和 Th17 (IL17+ CD4+) 细胞，挽救运动功能并防止多巴胺能神经元损失。这些结果强调了效应 CD4+ T 细胞（尤其是 Th17）在 PD 进展中的重要性，并为将用于关节炎的免疫调节药物重新用作 PD 修饰疗法提供了新的可能性。