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Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance and is among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1 requires quantitative analysis of their interactions at the cell surface. We present here the first completein situkinetic analysis of the PD-1/PD-ligands/B7-1 system. Consistent with previous solution measurements, we observed higherin situaffinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, thein situaffinities of PD-1 are as high as those of the T cell receptor for agonist pMHC and of LFA-1 (lymphocyte function-associated antigen 1) for ICAM-1 (intercellular adhesion molecule 1) but significantly lower than that of the B7-1/CTLA-4 interaction, suggesting a distinct basis for PD-1-versusCTLA-4-mediated inhibition. Notably, thein situinteractions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, thein situaffinity ranking greatly depends on the on-rate instead of the off-rate.In silicosimulations predict that PD-1/PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

Original publication




Journal article


J Biol Chem




6799 - 6809


T-cell, cell surface protein, kinetics, mathematical modeling, protein-protein interaction, Animals, B7-1 Antigen, CHO Cells, Cell Membrane, Cell Separation, Cricetinae, Cricetulus, Erythrocytes, Flow Cytometry, Humans, Intercellular Adhesion Molecule-1, Ligands, Lymphocyte Function-Associated Antigen-1, Mice, Models, Theoretical, Programmed Cell Death 1 Receptor, Protein Interaction Mapping, Receptors, Antigen, T-Cell, T-Lymphocytes