Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction

S Wang, J Bajorath, DB Flies, H Dong… - The Journal of …, 2003 - rupress.org
S Wang, J Bajorath, DB Flies, H Dong, T Honjo, L Chen
The Journal of experimental medicine, 2003rupress.org
B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and
B cell functions. These ligands, however, also costimulate T cell responses. It remains
elusive whether or not costimulation is mediated through PD-1. By comparative molecular
modeling and site-directed mutagenesis, we found that nonconserved residues between
these ligands on the A′ GFCC′ C′′ face mediate interaction with PD-1. This indicates
significant structural heterogeneity of the interactions between PD-1 and its ligands …
B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A′GFCC′C′′ face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1–deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.
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