title: IFN-gamma-receptor signaling ameliorates transplant vasculopathy through attenuation of CD8+ T-cell-mediated injury of vascular endothelial cells.
abstract: Occlusive transplant vasculopathy (TV) is the major cause for chronic graft rejection. Since endothelial cells (EC) are the first graft cells encountered by activated host lymphocytes, it is important to delineate the molecular mechanisms that coordinate the interaction of EC with activated T cells. Here, the interaction of CD8(+) T cells with Ag-presenting EC in vivo was examined using a transgenic heart transplantation model with beta-galactosidase (beta-gal) expression exclusively in EC (Tie2-LacZ hearts). We found that priming with beta-gal peptide-loaded DC failed to generate a strong systemic IFN-gamma response, but elicited pronounced TV in both IFN-gamma receptor (IFNGR)-competent, and ifngr(-/-) Tie2-LacZ hearts. In contrast, stimulation of EC-specific CD8(+) T cells with beta-gal-recombinant mouse cytomegalovirus (MCMV-LacZ) in recipients of ifngr(+/+) Tie2-LacZ hearts did not precipitate significant TV. However, MCMV-LacZ infection of recipients of ifngr(-/-) Tie2-LacZ hearts led to massive activation of beta-gal-specific CD8 T cells, and led to development of fulminant TV. Further analyses revealed that the strong systemic IFN-gamma "storm" associated with MCMV infection induced upregulation of programmed death-1 ligand 1 (PD-L1) on EC, and subsequent attenuation of programmed death-1 (PD-1)-expressing EC-specific CD8(+) T cells. Thus, IFNGR signaling in ECs activates a potent peripheral negative feedback circuit that protects vascularized grafts from occlusive TV.
authors.affiliation: Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bolinger
authors.forename: Daniel
authors.initials: D
authors.lastname: Engeler
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
authors.forename: Simone
authors.initials: S
authors.lastname: Miller
authors.forename: Sonja
authors.initials: S
authors.lastname: Firner
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor