title: The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors.
abstract: 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.
authors.affiliation: Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 2, 12441 Parklawn Drive, Rockville, MD 20852, USA.
authors.forename: David Yin-Wei
authors.initials: DY
authors.lastname: Lin
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Apostolos G
authors.initials: AG
authors.lastname: Gittis
authors.forename: Hua-Poo
authors.initials: HP
authors.lastname: Su
authors.forename: Bunzo
authors.initials: B
authors.lastname: Mikami
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
authors.forename: David N
authors.initials: DN
authors.lastname: Garboczi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D060890:B7-H1 Antigen; D019295:Computational Biology; D003460:Crystallization; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020539:Sequence Analysis, Protein; D017385:Sequence Homology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007135:Immunoglobulin Variable Region; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell