title: In situandin silicokinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network.
abstract: 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.
authors.affiliation: From the Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta 30332-0535, Georgia.
authors.forename: Kaitao
authors.initials: K
authors.lastname: Li
authors.affiliation: the Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Cheng
authors.affiliation: the Systems Biology Research Centre, School of Bioscience, University of Skövde, Box 408, Skövde, Sweden, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tilevik
authors.affiliation: the Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
authors.affiliation: the Coulter Department of Biomedical Engineering, the Woodruff School of Mechanical Engineering, and the Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta 30332-0535, Georgia cheng.zhu@bme.gatech.edu.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D006224:Cricetinae; D003412:Cricetulus; D004912:Erythrocytes / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D025941:Protein Interaction Mapping; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; C573420:ICAM1 protein, human; C090509:Icam1 protein, mouse; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1
keywords: T-cell; cell surface protein; kinetics; mathematical modeling; protein-protein interaction