Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.
The study demonstrates that MSA patients harbor clonally expanded, brain‑homing cytotoxic CD8+ (and CD4+) T cells that recognize α‑synuclein in an HLA‑dependent manner and exhibit inflammatory and cytotoxic transcriptional programs.
What the AI sees
The study demonstrates that MSA patients harbor clonally expanded, brain‑homing cytotoxic CD8+ (and CD4+) T cells that recognize α‑synuclein in an HLA‑dependent manner and exhibit inflammatory and cytotoxic transcriptional programs.
Research significance
By implicating antigen‑specific adaptive immunity against α‑synuclein and defining HLA‑restricted T cell clonotypes and effector programs, the work points to actionable targets (antigen presentation, T cell responses, biomarkers) for immunomodulatory or antigen‑specific therapies relevant to…
Source abstract
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 GZMB, GNLY, 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.