PD-1 and PD-L1 mediated immune checkpoint in synapse elimination by glia

Abstract

Glial cells in the brain regulate synaptic pruning by phagocytosing redundant synapses in the healthy brain

however, the mechanisms that signal to the glial cells to avoid engulfing necessary synapses remain unknown. In this study, we demonstrate that immune system’s “don’ eat me signal”, PD-1 and PD-L1, also protects synapses from being engulfed by glia. We found that PD-1 expression peaks in the hippocampus during early developmental period and that receptor expression is localized in astrocytes and microglia. The ligand, PD-L1, was found to be expressed on the synapses of neurons, specifically on both excitatory and inhibitory pre-synapses and excitatory post-synapses. PD-1 deficient mice exhibited increased PD-L1 expressions on pre-synapses, which were not correlated with the activation of astrocytes. In addition, in vitro engulfment assay showed PD-1-PD-L1 binding can reduce phagocytosis of synaptosome-pHrodo by astrocytes. Taken together, these results demonstrate PD-1-PD-L1 signaling inhibits astrocyte phagocytosis and that the molecular brakes of glia-mediated synapse elimination can be crucial for appropriate brain development.