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

With the widespread use of PD-1 inhibitors in the treatment of cancer patients, emerging clinical evidence has linked them to the onset of parkinsonism, raising critical questions about the role of PD-1 in Parkinson’s disease (PD) pathogenesis—a connection previously unexplored. Here, we found that PD-1 blockade aggravated, while its activation mitigated, dopaminergic neuronal damage and motor deficits in PD mouse models. Immunofluorescence and flow cytometry analyses revealed that PD-1 blockade promoted blood-brain barrier (BBB) permeabilization and drove neuroinflammation by enhancing cerebral infiltration of CD4 ⁺ T cell and a Th1-biased differentiation. Notably, these effects were reversed by PD-1 activation both in vivo and in vitro. We further identify the AKT/GSK3β signaling pathway in CD4 ⁺ T cells as the central mediator of this immunomodulatory effect. Clinically relevance demonstrated by dysregulated PD-1 and PD-L1 expression in peripheral CD4 ⁺ T cells from PD patients, with notable variation across clinical subtypes. Together, these findings demonstrated that PD-1 blockade-induced CD4 ⁺ T cell dysregulation exacerbates neuroinflammation and neurodegeneration in PD, providing a novel perspective on immune pathogenesis in PD and presenting a significant, mechanistic advance with translational implications.