Masubuchi Takeya, Chen Lin, Marcel Nimi, Wen George A, Caron Christine, Zhang Jibin, Zhao Yunlong, Morris Gerald P, Chen Xu, Hedrick Stephen M, Lu Li-Fan, Wu Chuan, Zou Zhengting, Bui Jack D, Hui Enfu
Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Sci Immunol. 2025 Jan 3;10(103):eads6295. doi: 10.1126/sciimmunol.ads6295.
Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8 T cells and increased the magnitude of anti-PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage-specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti-PD-(L)1 responses in mouse models and human patients.
对抑制性免疫受体程序性死亡蛋白1（PD-1）的机制理解在很大程度上基于小鼠模型，但人类和小鼠的PD-1氨基酸同一性仅为59.6%。在这里，我们发现人类PD-1比小鼠PD-1的抑制作用更强，这是由于它与配体程序性死亡配体1（PD-L1）和程序性死亡配体2（PD-L2）的相互作用更强，以及效应磷酸酶含Src同源2结构域蛋白2（Shp2）的募集更有效。在一个过继转移T细胞的小鼠黑色素瘤模型中，PD-1细胞内结构域的人源化破坏了CD8 T细胞的抗肿瘤活性，并增加了抗PD-1反应的强度。我们鉴定出一个在脊椎动物PD-1直系同源物中高度保守、在啮齿动物中不存在的基序，它是差异招募Shp2的关键决定因素。进化分析表明，PD-1在进化过程中经历了啮齿动物谱系特异性的功能衰减。总之，我们的研究揭示了PD-1通路的物种特异性特征，这对PD-1的进化以及小鼠模型和人类患者中抗PD-（L）1反应的差异具有启示意义。
