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Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-²õ²â²Ô³Ü³¦±ô±ð¾±²Ôopathy. 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 , , and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4 and CD8 T cells from MSA patients recognize α-²õ²â²Ô³Ü³¦±ô±ð¾±²Ô 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-²õ²â²Ô³Ü³¦±ô±ð¾±²Ô 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.