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

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