Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate Tcells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of Tcell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit Tcell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.