Suppressed T-cell activation by IFN-gamma-induced expression of PD-L1 on renal tubular epithelial cells.
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-gamma, 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-gamma-stimulated TEC. We speculate that the PD-1/PD-L1 pathway may play a role in protecting the epithelium from immune-mediated tubulointerstitial injury.
Schoop
Roland
R
Division of Nephrology, Kantonsspital St Gallen, Switzerland.
Wahl
Patricia
P
Le Hir
Michel
M
Heemann
Uwe
U
Wang
Minghui
M
Wüthrich
Rudolf P
RP
D000818:Animals; D017951:Antigen Presentation / Q000502:physiology; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000502:physiology
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007371:Interferon-gamma