PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity
PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity
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DOI：
10.1038/s41590-021-01125-7
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发表时间：
2022-02-10
影响因子：
30.5
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Sugiura, Daisuke;Okazaki, Il-mi;Okazaki, Taku
靶向阻断检查点分子程序性细胞死亡1（PD-1）可以激活肿瘤特异性T细胞以破坏肿瘤，而靶向增强PD-1有望抑制自身反应性T细胞并缓解自身免疫性疾病。然而，开发增强PD-1的方法仍然具有挑战性。在这里，我们通过靶向顺式-PD-L1-CD 80双链体成功地引发了PD-1功能，所述顺式-PD-L1-CD 80双链体通过CD 80与PD-1配体PD-L1结合形成，其减弱PD-L1-PD-1结合并消除PD-1功能。通过产生使CD 80与顺式PD-L1-CD 80双链体分离并使PD-L1在CD 80存在下与PD-1结合的抗CD 80抗体，我们证明了在PD-1功能受到限制的情况下，顺式PD-L1-CD 80双链体的靶向解离可增强PD-1功能。我们使用小鼠模型证明，PD-1限制的去除在减轻自身免疫性疾病症状方面是有效的。我们的研究结果建立了一种增强PD-1功能的方法，并提出了消除抑制机制作为增强抑制分子功能的有效策略。Okazaki及其同事开发并表征了协同T细胞PD-1活性的单克隆抗体。这些抗体可用于改善实验性自身免疫性疾病。
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.