title: Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses.
abstract: Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.
authors.affiliation: Institute of Physiology, Zürich Center for Integrative Human Physiology, University of Zürich, and Department of Urology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Starke
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Neusser
authors.forename: Barbara
authors.initials: B
authors.lastname: Rüsi
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Schmid
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehr
authors.forename: Ying
authors.initials: Y
authors.lastname: Waeckerle-Men
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D060890:B7-H1 Antigen; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008024:Ligands; D011506:Proteins; D016899:Interferon-beta