Cytotoxic T cell recognition of alpha-synuclein drives pathogenic immune responses in multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurologic disease, known as an alpha-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson disease and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8 T cells expressing GZMB, GNLY, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4 and CD8T cells from MSA patients recognize alpha-synuclein monomers and pre-formed fibrils in an HLA class I or II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8 T cell density was increased in the parietal cortex of post-mortem MSA brain tissues, along with cytotoxic (GZMB, GZMK) and pro-inflammatory (IFNgamma) CD8 T cells. Together, these findings demonstrate that cytotoxic T cells targeting alpha-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.

多系统萎缩（Multiple System Atrophy, MSA）是一种进行性神经系统疾病，属于α-突触核蛋白病（alpha-synucleinopathy）范畴。目前针对多系统萎缩尚无有效的疾病修饰治疗方案。尽管神经炎症是多系统萎缩的标志性病理特征，但适应性免疫机制在该病中的作用仍未被充分阐明。本研究针对多系统萎缩患者的外周及中枢T细胞应答展开系统性表征分析，同时与帕金森病患者队列及健康对照队列进行对比，所用技术包括单细胞转录组学、流式细胞术及抗原特异性功能实验。研究证实，多系统萎缩患者的外周T细胞处于活化状态，并偏向于细胞毒性与促炎表型。单细胞转录组分析进一步揭示，表达GZMB、GNLY以及与脑归巢相关的趋化因子和整合素基因程序的细胞毒性CD8 T细胞发生了克隆扩增。此外，本研究还证实，多系统萎缩患者的CD4及CD8 T细胞可通过人类白细胞抗原I类（HLA class I）或II类（HLA class II）分子限制性方式识别α-突触核蛋白单体与预形成纤丝，进而驱动细胞增殖、克隆扩增并获得细胞毒性特征。与上述外周免疫应答一致，死后多系统萎缩脑组织的顶叶皮层中CD8 T细胞密度显著升高，同时伴随细胞毒性（GZMB、GZMK）及促炎（IFNγ）表型的CD8 T细胞浸润。综上，本研究证实靶向α-突触核蛋白的细胞毒性T细胞参与了多系统萎缩的发病过程，提示其活性可能参与神经炎症与疾病进展，并强调该免疫轴可作为潜在治疗靶点以供后续深入研究。