{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:52:49Z","timestamp":1793213569184,"version":"4.5.0"},"reference-count":76,"publisher":"National Academy of Sciences","issue":"14","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR078268"],"award-info":[{"award-number":["R01AR078268"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI173189-01"],"award-info":[{"award-number":["AI173189-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["PATHO-PH2-SUB_17_23"],"award-info":[{"award-number":["PATHO-PH2-SUB_17_23"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brennan Family","award":["01"],"award-info":[{"award-number":["01"]}]},{"name":"Mission MSA CURE-MSA","award":["01"],"award-info":[{"award-number":["01"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:p>\n                    Multiple system atrophy (MSA) is a progressive neurologic disease, known as an \u03b1-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\u2019s 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\n                    <jats:sup>+<\/jats:sup>\n                    T cells expressing\n                    <jats:italic toggle=\"yes\">GZMB<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">GNLY<\/jats:italic>\n                    , and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells from MSA patients recognize \u03b1-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\n                    <jats:sup>+<\/jats:sup>\n                    T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB\n                    <jats:sup>+<\/jats:sup>\n                    , GZMK\n                    <jats:sup>+<\/jats:sup>\n                    ) and proinflammatory (IFN\u03b3\n                    <jats:sup>+<\/jats:sup>\n                    ) CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Together, these findings demonstrate that cytotoxic T cells targeting \u03b1-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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2537271123","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:02:15Z","timestamp":1774897335000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Cytotoxic T cell recognition of \u03b1-synuclein drives pathogenic immune responses in multiple system atrophy"],"prefix":"10.1073","volume":"123","author":[{"given":"Jae-Seung","family":"Moon","sequence":"first","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University","place":["Stanford"]},{"name":"VA Palo Alto Health Care System","place":["Palo 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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\u2019s and Massachusetts General Hospitals (Mass General Brigham)","place":["Boston"]},{"name":"Department of Neurology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"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\u2019s and Massachusetts General Hospitals (Mass General Brigham)","place":["Boston"]},{"name":"Department of Neurology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"El Kodsi","sequence":"additional","affiliation":[{"name":"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\u2019s and Massachusetts General Hospitals (Mass General Brigham)","place":["Boston"]},{"name":"Department of Neurology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5443-8540","authenticated-orcid":false,"given":"Anastasia","family":"Kuzkina","sequence":"additional","affiliation":[{"name":"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\u2019s and Massachusetts General Hospitals (Mass General Brigham)","place":["Boston"]},{"name":"Department of Neurology, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4319-1738","authenticated-orcid":false,"given":"Shady","family":"Younis","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University","place":["Stanford"]},{"name":"VA Palo Alto Health Care System","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaghayegh","family":"Jahanbani","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University","place":["Stanford"]},{"name":"VA Palo Alto Health Care System","place":["Palo 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of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease","volume":"119","author":"Brochard V.","year":"2008","unstructured":"V. Brochard , Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182\u2013192 (2008).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae177"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl6157"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01604-z"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf7266"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-025-02198-4"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab103"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","unstructured":"N. J. Corbin-Stein Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy. bioRxiv [Preprint] (2024) 10.1101\/2024.06.02.597035 (Accessed 3 June 2024).","DOI":"10.1101\/2024.06.02.597035"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02126-w"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12678"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062354"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1459884"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00437"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci13020205"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27041"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-023-01710-x"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.009"},{"key":"e_1_3_4_42_2","first-page":"1","article-title":"Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson\u2019s disease: An observational and case\u2013control study","volume":"1","author":"Kannarkat G.","year":"2015","unstructured":"G. Kannarkat , Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson\u2019s disease: An observational and case\u2013control study. NPJ Parkinson\u2019s Dis. 1, 1\u20139 (2015).","journal-title":"NPJ Parkinson\u2019s Dis."},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4633"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22815"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15626-w"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-025-03359-w"},{"key":"e_1_3_4_47_2","unstructured":"J. -S. Moon . Data from \u201cCytotoxic T cell recognition of a-synuclein drives pathogenic immune responses in multiple system atrophy\u201d NCBI Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1404663. 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Gu L. Gu R. Eils M. Schlesner B. Brors \u201cCirclize\u201d implements and enhances circular visualization in R. Bioinform. 30 2811\u20132812 (2014).","DOI":"10.1093\/bioinformatics\/btu393"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2537271123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:02:31Z","timestamp":1774897351000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2537271123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":76,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,4,7]]}},"alternative-id":["10.1073\/pnas.2537271123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2537271123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"assertion":[{"value":"2025-12-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2537271123"}}