Researchers found that deleting the immune checkpoint protein PD-1 in CD4+ T cells boosts antiviral activity in the brain while increasing neuroinflammation, according to a study published in Nature Communications.
T cells express programmed cell death protein 1 during progressive multifocal leukoencephalopathy, a life-threatening central nervous system infection caused by the human-only JC polyomavirus. Checkpoint immunotherapy targeting PD-1 has helped some patients with the condition, though clinical outcomes remain variable across cases.
Scientists investigated the mechanism using mouse polyomavirus models. The study showed that PD-1 loss acts in a brain-autonomous manner, expanding populations of brain-infiltrating CD4+ and CD8+ T cells while boosting the function of virus-specific CD8+ T cells. Brain viral levels dropped alongside these immune changes, while neuroinflammation increased.
Targeted deletion of PD-1 specifically in CD4+ T cells, rather than CD8+ T cells, reproduced the full effects of global PD-1 loss. Single-cell RNA sequencing revealed that PD-1-deficient CD8+ T cells clustered as effectors, upregulating transcripts associated with cell proliferation and function to balance antiviral protection against tissue injury.
Investigators at the Pennsylvania State University College of Medicine conducted the research alongside co-authors from McGill University, Brown University, and the University of Virginia. The study received support from the Canadian Institutes of Health Research and the National Institutes of Health before publication on August 17, 2026.
