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

Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-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's disease (PD) 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 <i>GZMB</i>, <i>GNLY</i>, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4⁺ and CD8⁺ T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/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 postmortem MSA brain tissues, along with cytotoxic (GZMB⁺, GZMK⁺) and proinflammatory (IFNγ⁺) CD8⁺ T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-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.