Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses
Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses
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DOI：
10.1126/science.aav7062
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发表时间：
2019-05-10
期刊：
影响因子：
56.9
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Sugiura, Daisuke;Maruhashi, Takumi;Okazaki, Taku
用免疫检查点抑制剂靶向阻断PD-1可以激活T细胞来摧毁肿瘤。PD-1被认为主要在效应器发挥作用，但不在T细胞反应的激活阶段，但PD-1在激活阶段的功能如何受到限制目前尚不清楚。在这里，我们证明了CD80与顺式抗原提呈细胞(APC)上的PD-L1相互作用，从而破坏PD-L1/PD-1结合。因此，当APC表达大量CD80时，PD-L1不能与PD-1结合来抑制T细胞的激活。在不发生cis-PD-L1/CD80相互作用的敲入小鼠中，PD-1显著减弱了肿瘤免疫和自身免疫反应。这些发现表明，APC上的CD80限制了PD-1共抑制信号，而促进了CD28介导的共刺激作用，并突出了诱导最佳免疫反应的关键成分。
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.