Journal Article

PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity

Shimizu Kenji, Takemoto Tatsuya, Okazaki Taku, Arakaki Rieko, Sugiura Daisuke, Maruhashi Takumi, Ishimaru Naozumi, Maeda, Takeo K, Il-mi, Okazaki

2022

Overview

Targeted blockade of the checkpoint molecule programmed cell death 1 (PD-1) can activate tumor-specific T cells to destroy tumors, whereas targeted potentiation of PD-1 is expected to suppress autoreactive T cells and alleviate autoimmune diseases. However, the development of methods to potentiate PD-1 remains challenging. Here we succeeded in eliciting PD-1 function by targeting the cis-PD-L1–CD80 duplex, formed by binding of CD80 to the PD-1 ligand PD-L1, that attenuates PD-L1–PD-1 binding and abrogates PD-1 function. By generating anti-CD80 antibodies that detach CD80 from the cis-PD-L1–CD80 duplex and enable PD-L1 to engage PD-1 in the presence of CD80, we demonstrate that the targeted dissociation of cis-PD-L1–CD80 duplex elicits PD-1 function in the condition where PD-1 function is otherwise restricted. We demonstrate using murine models that the removal of PD-1 restriction is effective in alleviating autoimmune disease symptoms. Our findings establish a method to potentiate PD-1 function and propose the removal of restraining mechanisms as an efficient strategy to potentiate the function of inhibitory molecules.Okazaki and colleagues develop and characterize monoclonal antibodies that co-opt T cell PD-1 activity. These antibodies can be used to ameliorate experimental autoimmune disease.

• Publisher: Nature Publishing Group
• Subject: Animal models / Antibodies / Apoptosis / Autoimmune diseases / Autoimmunity / CD80 antigen / Cell activation / Cell death / Lymphocytes T / Monoclonal antibodies / PD-1 protein / PD-L1 protein