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Molecular Modeling and Functional Mapping of B7-H1 and B7-DC Uncouple Costimulatory Function from PD-1 Interaction

Shengdian Wang¹, Jürgen Bajorath^2,3, Dallas B. Flies¹, Haidong Dong¹, Tasuku Honjo⁴ and Lieping Chen¹

¹ Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, MN 55905
² Albany Molecular Research Inc., Bothell Research Center, Bothell, WA 98011
³ Department of Biological Structure, University of Washington, Seattle, WA 98195
⁴ Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

Address correspondence to Lieping Chen, Department of Immunology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: 507-538-0013; Fax: 507-284-1637; E-mail: chen.lieping{at}mayo.edu

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.

Key Words: PD-1 ligands • mutagenesis • costimulation • T cell activation

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