Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses
D Sugiura, T Maruhashi, I Okazaki, K Shimizu… - Science, 2019 - science.org
D Sugiura, T Maruhashi, I Okazaki, K Shimizu, TK Maeda, T Takemoto, T Okazaki
Science, 2019•science.orgTargeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy
tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of
T cell 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 T cell activation when APCs express substantial amounts of CD80. In knock-in mice in …
tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of
T cell 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 T cell activation when APCs express substantial amounts of CD80. In knock-in mice in …
Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell 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 T cell 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.
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