ABSTRACT
Programmed cell death protein 1 (PD-1) is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment. Accumulating evidence suggests an important role of PD-1 in the central nervous system (CNS). PD-1 has been implicated in CNS disorders such as brain tumors, Alzheimer’s disease, ischemic stroke, spinal cord injury, multiple sclerosis, cognitive function, and pain. PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells. Notably, PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function. An improved understanding of PD-1 signaling in the cross-talk between glial cells, neurons, and peripheral immune cells in the CNS will shed light on immunomodulation, neuromodulation, and novel strategies for treating brain diseases.