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.