As mouse PD-1 (muPD-1) only shares 59.6% amino acid identity with human PD-1 (huPD-1), Masubuchi et al. compared signal strength of the two receptors in quantitative assays. HuPD-1 was more inhibitory than muPD-1 due to stronger binding to PD-L1 and PD-L2, and was more efficient in recruiting Shp2. In a melanoma model, humanization of the intracellular domain of muPD-1 decreased the antitumor activity of adoptively transferred CD8+ T cells and increased the efficacy of anti-PD-1 treatment. A motif upstream of the ITSM domain, important for Shp2 binding, was missing in rodents, suggesting species–specific evolutionary attenuation.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (2) Key Laboratory of Zoological Syste
Author Info: (1) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (2) Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. (3) Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (4) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (5) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. (6) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (7) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (8) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. (9) Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA. (10) Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (11) Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. (12) Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (13) Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. (14) Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA. (15) Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
