Engagement of the immune checkpoint receptor PD-1 by its ligand PD-L1 triggers recruitment and activation of the phosphatase SHP2, which dephosphorylates T cell receptor (TCR) components and costimulatory signaling pathways. In Science Immunology, Masubuchi et al. show that mouse PD-1 has a reduced inhibitory function compared with human PD-1. Titration experiments in human Jurkat T cells, mouse DO11.10 T cells or primary human CD4+ T cells expressing equivalent amounts of tagged PD-1 indicated that human PD-1–PD-L1 was more suppressive of IL-2 expression than mouse PD-1–PD-L1 across various TCR signaling strengths. Human PD-1 had 3.2-fold higher affinity for PD-L1, 24-fold higher affinity for PD-L2, 2.9-fold stronger affinity for SHP2, and clustered more at the antigen presenting cell (APC)–T cell interface than mouse PD-1. Weaker SHP2 binding in mouse PD-1 was mostly due to replacement of the Pro-Glu-Gln (PEQ) motif upstream of the SHP2-docking site with a His residue. Melanoma-inoculated mice transferred with T cells that expressed mouse PD-1 in which the intracellular domain was humanized or in which the His was replaced by the human PEQ sequence had faster tumor growth and less infiltration by T cells, which had reduced Gzmb and increased Tcf7 expression. Thus, human PD-1 restricts the proliferation, effector function and precursor-to-terminal transition of exhausted T cells more potently than mouse PD-1.

Original reference: Sci. Immunol. https://doi.org/10.1126/sciimmunol.ads6295 (2025)