PD-1 regulates CD4⁺ T cell-mediated CD8⁺ T cell responses in the brain to balance viral control and neuroinflammation

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain CD4⁺ and CD8⁺ T cells are PD-1^high during mouse polyomavirus (MuPyV) encephalitis. Here, we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4⁺ and CD8⁺ T cells and the function of virus-specific CD8⁺ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4⁺ T cells, but not CD8⁺ T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8⁺ T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4⁺ T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus CNS infection.