USP2 safeguards retinal homeostasis by stabilizing macrophage PD-L1 to restrain CD8⁺ T cell cytotoxicity in age-related macular degeneration

Background Age-related macular degeneration (AMD) is driven by chronic oxidative injury and immune dysregulation within the retinal microenvironment, yet the post-translational mechanisms governing immune homeostasis remain incompletely understood. Deubiquitinating enzymes (DUBs) have emerged as critical regulators of protein stability, but their roles in retinal immunity and AMD pathogenesis have not been systematically explored. Results Through integrated bioinformatic and experimental screening, we identified ubiquitin-specific protease 2 (USP2) as a retina-enriched DUB that is consistently downregulated in AMD patients, oxidative stress-induced murine models, and aged retinas, with depletion most pronounced in the synaptic plexiform layers and the RPE/choroid interface—regions critical for immune regulation. Genetic ablation of Usp2 exacerbated RPE damage and retinal degeneration following oxidative injury, whereas USP2 overexpression conferred robust protection. Mechanistically, USP2 directly bound to PD-L1 on retinal macrophages and removed its ubiquitin chains, thereby preventing proteasomal degradation and sustaining PD-L1 surface expression. Loss of USP2 destabilized macrophage PD-L1, which unleashed CD8⁺ cytotoxic T lymphocyte infiltration and activation, driving RPE injury through macrophage–T cell crosstalk. Critically, pharmacological activation of the PD-1 inhibitory pathway with peresolimab effectively attenuated oxidative damage, preserved RPE integrity, and recapitulated the protective effects of USP2 augmentation. Conclusions The USP2–PD-L1 axis constitutes a previously unrecognized antioxidant immune checkpoint that couples redox stress to adaptive immune suppression within the retina. Oxidative stress-induced disruption of this deubiquitination-dependent checkpoint emerges as a critical driver of AMD progression, positioning USP2 and its downstream PD-L1/PD-1 pathway as promising immunomodulatory targets for therapeutic intervention in degenerative retinal diseases.