Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Jae-Seung Moon
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Salvinaz I. Moutusy
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Mengrui Zhang
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Alain Ndayisaba
Division of Movement Disorders Harvard Biomarkers Study 2.0 (HBS 2.0) and MyTrial Programs, American Parkinson Disease Association, Center for Advanced Research and MSA Center of Excellence, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s and Massachusetts General Hospitals (Mass General Brigham)
Diego Rodriguez
Division of Movement Disorders Harvard Biomarkers Study 2.0 (HBS 2.0) and MyTrial Programs, American Parkinson Disease Association, Center for Advanced Research and MSA Center of Excellence, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s and Massachusetts General Hospitals (Mass General Brigham)
Daniel N. El Kodsi
Division of Movement Disorders Harvard Biomarkers Study 2.0 (HBS 2.0) and MyTrial Programs, American Parkinson Disease Association, Center for Advanced Research and MSA Center of Excellence, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s and Massachusetts General Hospitals (Mass General Brigham)
Anastasia Kuzkina
Division of Movement Disorders Harvard Biomarkers Study 2.0 (HBS 2.0) and MyTrial Programs, American Parkinson Disease Association, Center for Advanced Research and MSA Center of Excellence, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s and Massachusetts General Hospitals (Mass General Brigham)
Shady Younis
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine
Shaghayegh Jahanbani
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Laura S. van Dam
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Ya’el Courtney
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Adi Netanel
VA Palo Alto Health Care System
Orr Sharpe
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
Mitchell G. Miglis
Department of Neurology and Neurological Sciences, Stanford University
Lawrence Steinman
Department of Neurology and Neurological Sciences, Stanford University
Vikram Khurana
Division of Movement Disorders Harvard Biomarkers Study 2.0 (HBS 2.0) and MyTrial Programs, American Parkinson Disease Association, Center for Advanced Research and MSA Center of Excellence, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s and Massachusetts General Hospitals (Mass General Brigham)
Fereshteh Jahanbani
Division of Immunology and Rheumatology, Department of Medicine, Stanford University
William H. Robinson