Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal

Nat Immunol. 2009 Nov;10(11):1185-92. doi: 10.1038/ni.1790. Epub 2009 Sep 27.

Abstract

Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Surface / immunology*
  • Antigens, Surface / metabolism
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • B7-1 Antigen / immunology*
  • B7-1 Antigen / metabolism
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cell Movement
  • Dendritic Cells / immunology
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Immune Tolerance*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Peptides / immunology*
  • Peptides / metabolism
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology*

Substances

  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cd274 protein, mouse
  • Ctla4 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell