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In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network
Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, USA.
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. (Infektionsbiologi, Infection Biology)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
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2017 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, nr 16, s. 6799-6809Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 complete in situ kinetic analysis of the PD-1/PD-ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities 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, the in situ affinities 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- versus CTLA-4-mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations 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.

Ort, förlag, år, upplaga, sidor
American Society for Biochemistry and Molecular Biology, Inc. , 2017. Vol. 292, nr 16, s. 6799-6809
Nyckelord [en]
T-cell, cell surface protein, kinetics, mathematical modeling, protein-protein interaction
Nationell ämneskategori
Immunologi
Forskningsämne
Infektionsbiologi; INF000
Identifikatorer
URN: urn:nbn:se:his:diva-13534DOI: 10.1074/jbc.M116.763888ISI: 000399813400030PubMedID: 28270509Scopus ID: 2s2.0-85018570744OAI: oai:DiVA.org:his-13534DiVA, id: diva2:1091918
Tillgänglig från: 2017-04-28 Skapad: 2017-04-28 Senast uppdaterad: 2019-11-25Bibliografiskt granskad

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Tilevik, Andreas

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