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

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 a-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. Overall design: Eighteen-month-old WT and CD200R1?/? mice were used to investigate the role of CD200R1 in neuroinflammation and T cell–mediated neurodegeneration. Brain tissues were collected for immune profiling and transcriptomic analysis. CD11b? cells were isolated using magnetic separation, and cell viability, concentration, and clumping were assessed using acridine orange/propidium iodide staining and automated fluorescence cell counting. Single-cell suspensions (18,228 cells from WT and 19,159 from CD200R1?/?) were processed with the 10x Genomics Chromium system for single-cell RNA-seq.