PD-1 blockade exacerbates CD4+ T-cell dysregulation and dopaminergic neurodegeneration in Parkinson’s disease

With the widespread use of PD-1 inhibitors in cancer therapy, emerging evidence has linked them to the onset of parkinsonism, raising unexplored questions about PD-1 in Parkinson’s disease (PD) pathogenesis. Here, we found that PD-1 blockade exacerbated, while PD-L1-Fc treatment mitigated, dopaminergic (DA) neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. Similarly, in A53T transgenic PD mice, PD-1 blockade aggravated α-synuclein pathology and motor dysfunction, both of which were reversed by PD-L1-Fc administration. Mechanistically, PD-1 blockade compromised blood-brain barrier (BBB) integrity, promoted cerebral CD4⁺ T cell infiltration, and skewed Th1/Treg differentiation, whereas PD-L1-Fc treatment reversed these effects. Notably, CD4⁺ T cell depletion abrogated PD-1 blockade-associated DA neuron loss in the MPTP model, establishing CD4⁺ T cells as the critical mediators of this immunopathological process. We further demonstrated that AKT/GSK3β phosphorylation in CD4⁺ T cells mediated PD-1's modulation of CD4⁺ T cell homeostasis. Collectively, our findings reveal that PD-1 blockade exacerbates neurodegeneration and α-synuclein pathology via CD4⁺ T cell-associated immune dysregulation, offering insights into PD immune mechanisms and therapeutic strategies.