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J Biol Chem. 2017 Apr 21;292(16):6799-6809. doi: 10.1074/jbc.M116.763888. Epub 2017 Mar 6.

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.

Author information

1
From the Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta 30332-0535, Georgia.
2
the Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
3
the Systems Biology Research Centre, School of Bioscience, University of Skövde, Box 408, Skövde, Sweden, and.
4
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.

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 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.

KEYWORDS:

T-cell; cell surface protein; kinetics; mathematical modeling; protein-protein interaction

PMID:
28270509
PMCID:
PMC5399126
DOI:
10.1074/jbc.M116.763888
[Indexed for MEDLINE]
Free PMC Article

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