Aging-associated decline in neuronal PD-L1 expression augments CD8+ T cell-mediated neuroinflammation

Abstract The healthy young brain is free of lymphocyte infiltration, yet this protection declines with aging. Accumulation of peripheral lymphocytes in the aged brain is linked to increased neuroinflammation and neurodegeneration. Whether brain-specific factors limit lymphocyte infiltration, proliferation and activation in the brain, thereby protecting it from inflammatory damage, remains unknown. Here, we identified the programmed death ligand 1 (PD-L1) as a key factor restricting lymphocyte accumulation in the brain. PD-L1 is selectively expressed in neurons and declines with age in both humans and mice, correlating with the accumulation of CD8⁺ T cells in the aging brain. Genetic ablation or pharmacological blockade of PD-L1 in young mice recapitulated aged brain phenotypes, such as increased CD8⁺ T cell infiltration, enhanced IFN-γ and granzyme B production, and impaired cognition. Mechanistically, these age-dependent phenotypes were mediated by ubiquitination-dependent degradation of PD-L1, driven by upregulation of UBR4 E3 ligase expression. Restoration of neuronal PD-L1 expression in aged mice via adeno-associated virus transduction mitigated neuroinflammation and rescued cognitive decline. Our findings establish neuronal PD-L1 as a guardian of brain immune homeostasis, which is compromised during aging.