Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart

Circulation. 2007 Oct 30;116(18):2062-71. doi: 10.1161/CIRCULATIONAHA.107.709360. Epub 2007 Oct 15.

Abstract

Background: PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart.

Methods and results: Cytotoxic T-lymphocyte-mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2-deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell-derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2(-/-)], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2(-/-) mice reconstituted with bone marrow from wild-type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency.

Conclusions: Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune-mediated cardiac injury and polymorphonuclear leukocyte inflammation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B7-1 Antigen / biosynthesis
  • B7-1 Antigen / genetics
  • B7-1 Antigen / physiology*
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocarditis / immunology
  • Myocarditis / metabolism*
  • Myocarditis / pathology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Peptides / genetics
  • Peptides / physiology*
  • Signal Transduction / immunology

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Inflammation Mediators
  • Membrane Glycoproteins
  • Peptides