Suppressed T-cell activation by IFN-γ-induced expression of PD-L1 on renal tubular epithelial cells

• Published in: Nephrology, dialysis, transplantation Vol. 19; no. 11; pp. 2713 - 2720
• Main Authors: Schoop, Roland, Wahl, Patricia, Le Hir, Michel, Heemann, Uwe, Wang, Minghui, Wüthrich, Rudolf P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2004
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; antigen presentation; Antigen Presentation - physiology; B7-1 Antigen - metabolism; B7-H1 Antigen; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Blotting, Western; Cells, Cultured; co-stimulation; Emergency and intensive care: renal failure. Dialysis management; Epithelial Cells - metabolism; Flow Cytometry; Intensive care medicine; Interferon-gamma - pharmacology; Kidney Tubules - cytology; Kidney Tubules - metabolism; Lymphocyte Activation - physiology; Male; Medical sciences; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; PD-1; PD-L1; PD-L2; Peptides - metabolism; Programmed Cell Death 1 Ligand 2 Protein; Renal failure; renal tubular epithelial cells; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes - immunology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Up-Regulation - physiology; Kidney disease; Urinary system disease; antigen presentation; Hemodialysis; renal tubular epithelial cells; co-stimulation; Extrarenal dialysis; Renal failure; T-Lymphocyte; PD-L1; Epithelial cell; PD-L2; Carbon monoxide; PD-1
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfh423

Background. The interaction of the T-cell molecule PD-1 (programmed death-1) with its ligands PD-L1 and PD-L2 represents a known mechanism of T-cell inhibition. PD-1 is homologous to CD28 while the PD-1 ligands share homology with the B7 family of co-stimulatory molecules. Methods. We have studied surface expression and transcript levels of PD-L1 and PD-L2 on murine renal tubular epithelial cells (TEC) by flow cytometric analysis and reverse transcription–polymerase chain reaction. Western blot analysis was used to confirm protein expression of PD-L1. We also tested the functional role of PD-L1 and PD-1 in antigen presentation. Furthermore, we stained mouse kidney transplants with rejection for the expression of the PD-1 ligands. Results. We found that PD-L1 but not PD-L2 was weakly expressed on unstimulated TEC. Upon stimulation with IFN-γ, a dose-dependent upregulation of PD-L1 expression was observed. Blockade of the PD-L1/PD-1 pathway with monoclonal antibodies in antigen presentation assays uncovered an inhibitory role of this ligand system in Th1 and Th2 cell activation. Staining for PD-L1 was strong in proximal and distal tubules in mouse kidney transplants with rejection, whereas staining of normal kidneys and syngenic mouse kidney transplants did not reveal PD-L1 expression. PD-L2 was not observed in normal or rejected mouse kidneys. Conclusions. These data demonstrate that PD-L1 is an inducible renal tubular epithelial antigen that negatively regulates T-cell responses elicited by IFN-γ-stimulated TEC. We speculate that the PD-1/PD-L1 pathway may play a role in protecting the epithelium from immune-mediated tubulointerstitial injury.