Objective: To define α-synuclein-specific peripheral T cell responses in multiple system atrophy (MSA) in comparison with parkinson’s disease (PD) and healthy controls (HC), and to assess CD8⁺ T cell presence in post-mortem MSA brain tissue.

Background: MSA is a rapidly progressive, fatal α-synucleinopathy marked by autonomic failure, parkinsonism, and cerebellar ataxia, with no disease-modifying therapies. Pathologically, MSA features fibrillar α-synuclein accumulation in oligodendroglia forming glial cytoplasmic inclusions, distinct from the neuronal Lewy bodies of PD. Although neuroinflammation and immune dysregulation are recognized across synucleinopathies, the contribution of adaptive immunity in MSA remains unclear. Prior studies suggest immune activation, but whether MSA T cells show α-synuclein specificity, clonal expansion, and cytotoxic effector programs has not been comprehensively examined.

Method: Peripheral T cell responses from patients with MSA were profiled in comparison with PD and HC cohorts using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. Single-cell RNA sequencing assessed activation, cytotoxic and inflammatory programs, and clonal expansion of T cells. Functional assays tested T cell responses to α-synuclein monomers and pre-formed fibrils with HLA class I/II dependence. Post-mortem parietal cortex from MSA and HC was analyzed to quantify CD8⁺ T cell density and cytotoxic/pro-inflammatory subsets.

Results: Peripheral T cells from MSA patients were strongly activated and skewed toward cytotoxic/inflammatory phenotypes, comparable to PD and higher than HC. scRNA-seq showed clonal expansion of GZMB⁺GNLY⁺ cytotoxic CD8⁺ T cells with chemokine/integrin trafficking programs. Functionally, CD4⁺ and CD8⁺ T cells recognized α-synuclein monomers and fibrils in an HLA class I/II–dependent manner, inducing proliferation, clonal expansion, and cytotoxic features. Post-mortem MSA parietal cortex showed increased CD8⁺ T cell density versus HC, including GZMB⁺/GZMK⁺ and IFNγ⁺ subsets.

Conclusion: α-synuclein-reactive cytotoxic T cells are engaged in MSA and coincide with increased CD8⁺ T cells in affected brain regions, suggesting a potential role in neuroinflammation and progression. These findings support this immune axis as a candidate for biomarker development and translational therapeutic targeting in MSA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-modal-profiling-of-peripheral-and-central-nervous-system-t-cells-identifies-cytotoxic-%ce%b1-synuclein-reactive-immunity-in-multiple-system-atrophy/