Functional differences between rodent and human PD-1 linked to evolutionary divergence.

Abstract

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.

Authors

Takeya Masubuchi, Lin Chen, Nimi Marcel, George A Wen, Christine Caron, Jibin Zhang, Yunlong Zhao, Gerald P Morris, Xu Chen, Stephen M Hedrick, Li-Fan Lu, Chuan Wu, Zhengting Zou, Jack D Bui, Enfu Hui

Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.