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.

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Together our data reveal that the renal PD-L1/PD-1 pathway has a negative effect on CD8+ CTL activation. PD-L1 might, therefore, act as a protective molecule on TEC, downregulating the cytotoxic renal parenchymal immune response.

Background/Aim: TGF-β expression is increased in immune-mediated and fibrotic renal diseases and modulates the tubulointerstitial T-cell response. We examined whether TGF-β changes the expression of PD-L1 and CD40 in the renal proximal tubular epithelial cell (TEC), and whether the activation of CD8⁺ cytotoxic T cells (CTLs) is influenced by TGF-β treatment of TECs. Methods: Murine TECs were treated with TGF-β or IFN-γ. The expression of PD-L1 and CD40 was examined with RT-PCR and flow cytometry. To investigate if TGF-β treatment influenced the antigen presentation capacity of TECs, OT-1 CTLs were co-incubated with TGF-β-treated, OVA_257–264 peptide-pulsed congeneic TECs. The cytotoxicity of OT-1 CTLs was estimated by their capacity to produce IFN-γ and their cytolytic activity. Results: TGF-β treatment lead to a transition in morphology of renal TECs and downregulated the basal and the IFN-γ-stimulated PD-L1 expression in TECs. Interestingly, TGF-β treatment of TECs increased the constitutive and IFN-γ-induced CD40 expression. In contrast to IFN-γ which reduced the CTL activity, TGF-β treatment of TECs elevated the OVA-specific CTL response. Conclusion: Our data show that TGF-β changed the cellular phenotype and the expression of PD-L1 and CD40 on TECs and enhanced the activity of OVA peptide-specific CD8⁺ T cells. TGF-β may thereby play an important role in the progression of renal tubulointerstitial damage in CD8⁺ T-cell-mediated renal diseases.