In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction networkShow others and affiliations
2017 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 16, p. 6799-6809Article in journal (Refereed) 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.
Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, Inc. , 2017. Vol. 292, no 16, p. 6799-6809
Keywords [en]
T-cell, cell surface protein, kinetics, mathematical modeling, protein-protein interaction
National Category
Immunology
Research subject
Infection Biology; INF000
Identifiers
URN: urn:nbn:se:his:diva-13534DOI: 10.1074/jbc.M116.763888ISI: 000399813400030PubMedID: 28270509Scopus ID: 2-s2.0-85018570744OAI: oai:DiVA.org:his-13534DiVA, id: diva2:1091918
Note
CC BY 4.0
2017-04-282017-04-282022-05-31Bibliographically approved