CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease

CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease Ting Zhang, Zhen Zhang, Kun Niu, Taoying Huang, Jiali Guo, Xiaoli Gong, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7253835/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Immune dysregulation is increasingly recognized as a key contributor to Parkinson’s disease (PD) pathogenesis. While microglia are established central nervous system (CNS) immune regulators, the role of CNS-associated macrophages (CAMs) and their upstream modulation by immune checkpoints remains poorly defined. Here, we identify CD200R1, a myeloid-specific inhibitory receptor, as a checkpoint selectively expressed by embryonically derived CAMs at CNS borders. CD200R1 deletion reprograms CAMs toward a proinflammatory, antigen-presenting state enriched in interferon and pyroptosis-related gene signatures. In α-synuclein–based PD models, CD200R1 loss exacerbates dopaminergic neurodegeneration, enhances CD8⁺ T cell infiltration, and promotes formation of tertiary microglial–T cell nodules. Mechanistically, it activates the caspase-8/GSDMD pyroptosis pathway in CAMs, creating a permissive environment for pathogenic T cells. Pyroptosis blockade with disulfiram attenuates T cell infiltration and neurodegeneration. Notably, pharmacological activation of CD200R1 via CD200Fc suppresses CAM activation and confers neuroprotection. These findings define a border-specific immune checkpoint that governs CAM–T cell crosstalk and represents a tractable therapeutic target in PD. Biological sciences/Neuroscience/Neuroimmunology Biological sciences/Immunology/Inflammation Full Text Additional Declarations There is NO Competing Interest. Ethics Statement All animal experiments in this study were reviewed, approved, and overseen by the Animal Experimentation Committee of Capital Medical University (Approval No. AEEI-2022-293). All procedures were performed in accordance with the committee’s ethical guidelines and the principles of the 3Rs (Replacement, Reduction, and Refinement). Mice were housed under specific pathogen-free (SPF) conditions in the Capital Medical University animal care facility, maintained on a 12-hour light/dark cycle with ad libitum access to food and water. Appropriate measures, including the use of anesthetics and analgesics when necessary, were taken to minimize pain and distress. Humane endpoints were applied, and animals were euthanized in accordance with approved protocols. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7253835","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":494384911,"identity":"60e97383-9ae4-4805-8c5d-a8f7759d349e","order_by":0,"name":"Ting 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While microglia are established central nervous system (CNS) immune regulators, the role of CNS-associated macrophages (CAMs) and their upstream modulation by immune checkpoints remains poorly defined. Here, we identify CD200R1, a myeloid-specific inhibitory receptor, as a checkpoint selectively expressed by embryonically derived CAMs at CNS borders. CD200R1 deletion reprograms CAMs toward a proinflammatory, antigen-presenting state enriched in interferon and pyroptosis-related gene signatures. In α-synuclein–based PD models, CD200R1 loss exacerbates dopaminergic neurodegeneration, enhances CD8⁺ T cell infiltration, and promotes formation of tertiary microglial–T cell nodules. Mechanistically, it activates the caspase-8/GSDMD pyroptosis pathway in CAMs, creating a permissive environment for pathogenic T cells. Pyroptosis blockade with disulfiram attenuates T cell infiltration and neurodegeneration. 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