T-cell and B-cell Immunology
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It is 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.
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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.
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@article{Masubuchi2025Functional,
title = {Functional differences between rodent and human PD-1 linked to evolutionary divergence},
author = {Takeya Masubuchi and Lin Chen and Nimi Marcel and George A. Wen and Christine Caron and Jibin Zhang and Yunlong Zhao and Gerald P. Morris and Xu Chen and Stephen Μ. Hedrick and Li‐Fan Lu and Chuan Wu and Zhengting Zou and Jack D. Bui and Enfu Hui},
journal = {Science Immunology},
year = {2025},
doi = {10.1126/sciimmunol.ads6295},
url = {https://doi.org/10.1126/sciimmunol.ads6295}
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