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

Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3011-6. doi: 10.1073/pnas.0712278105. Epub 2008 Feb 14.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / genetics
  • Antigens, CD / chemistry
  • Antigens, CD / genetics*
  • Antigens, CD / immunology
  • Antigens, Differentiation / chemistry
  • Antigens, Differentiation / genetics*
  • Antigens, Differentiation / immunology
  • B7-H1 Antigen
  • Computational Biology
  • Crystallization
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunoglobulin Variable Region / genetics*
  • Immunoglobulin Variable Region / immunology
  • Mice
  • Models, Molecular*
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell / genetics
  • Sequence Analysis, Protein
  • Sequence Homology
  • Signal Transduction / immunology*

Substances

  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation
  • B7-H1 Antigen
  • CD274 protein, human
  • Immunoglobulin Variable Region
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell

Associated data

  • PDB/3BIK
  • PDB/3BIS