Journal Article

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

Maruhashi, Takumi, Okazaki, Taku, Maeda, Takeo K., Okazaki, Il-mi, Shimizu, Kenji, Sugiura, Daisuke, Takemoto, Tatsuya

2019

Overview

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 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 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Animals / Antigen-presenting cells / Apoptosis / Autoimmunity / B7-1 Antigen - genetics / B7-1 Antigen - metabolism / B7-H1 Antigen - metabolism / Binding / Cancer / CD28 antigen / CD28 Antigens - metabolism / CD80 antigen / Cell activation / Cell death / Critical components / Dendritic cells / Dendritic Cells - immunology / Gene Knock-In Techniques / Humans / Immune checkpoint inhibitors / Immune response (cell-mediated) / Immunity / Immunotherapy / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Mice / Mice, Mutant Strains / Neoplasms - immunology / Neoplasms - therapy / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor - metabolism / Protein Binding / RESEARCH ARTICLE / T-Lymphocytes - immunology / Tumors