PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (8), p.3011-3016
• Main Authors: Lin, David Yin-wei, Tanaka, Yoshimasa, Iwasaki, Masashi, Gittis, Apostolos G, Su, Hua-Poo, Mikami, Bunzo, Okazaki, Taku, Honjo, Tasuku, Minato, Nagahiro, Garboczi, David N
• Format: Article
• Language: English
• Subjects: Animals; ANTIBODIES; Antibodies - genetics; Antigens; Antigens, CD - chemistry; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, Differentiation - chemistry; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; B7-H1 Antigen; Binding sites; Biological Sciences; Computational Biology; CRYSTAL STRUCTURE; Crystallization; Crystals; DESIGN; DRUGS; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; HUMAN POPULATIONS; Humans; Immune system; IMMUNITY; Immunoglobulin Variable Region - genetics; Immunoglobulin Variable Region - immunology; INTERACTIONS; Ligands; MAINTENANCE; MAPPING; MATERIALS SCIENCE; Mice; Models, Molecular; MOLECULES; Mutation; MUTATIONS; NEOPLASMS; Programmed Cell Death 1 Receptor; PROTEINS; RECEPTORS; Receptors, Antigen, T-Cell - genetics; RESIDUES; Sequence Analysis, Protein; Sequence Homology; Signal Transduction - immunology; SURFACES; T cell receptors; T lymphocytes; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712278105

Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives "exhausted" virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.