PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1

Int Immunol. 2010 Aug;22(8):651-60. doi: 10.1093/intimm/dxq049. Epub 2010 Jun 29.


The programmed death-1 (PD-1) molecule is involved in peripheral tolerance and in the immune escape mechanisms during chronic viral infections and cancer. PD-1 interacts with two ligands, PD-L1 and PD-L2. We have investigated the molecular mechanisms of PD-1 interactions with its ligands by surface plasmon resonance and cell surface binding as well as the ability of the two ligands to compete for PD-1 binding. PD-L1 and PD-L2 bound PD-1 with comparable affinities, but striking differences were observed at the level of the association and dissociation characteristics. PD-L1, but not PD-L2, had a delayed interaction reminiscent of a phenomenon of conformational transition. These mechanisms were confirmed by using PD-L1 mAbs that delayed the dissociation of PD-L1 from PD-1. This mechanism was not restricted to PD-1 binding since PD-L1 behaved in a similar manner with its second ligand, CD80. Finally, we could demonstrate that PD-L1 and PD-L2 competed for PD-1 binding and conversely, an antagonist PD-1 mAb blocked both PD-L1 and PD-L2 binding to PD-1 and strongly enhanced T-cell proliferation. These data further emphasize the differential molecular mechanisms of interaction of PD-L1 and PD-L2 with PD-1, and suggest possible new approach for the therapy of chronic infection, cancer and transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology*
  • B7-H1 Antigen
  • Cell Proliferation
  • Dendritic Cells / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology*
  • Polymerase Chain Reaction
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Protein Binding
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • Antibodies, Monoclonal
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • B7-H1 Antigen
  • CD274 protein, human
  • Intercellular Signaling Peptides and Proteins
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor