The co-inhibitory molecule PD-L1 contributes to regulatory T cell-mediated protection in murine crescentic glomerulonephritis

Katrin Neumann,Gisa Tiegs,Hans-Joachim Paust,Ulf Panzer,Frank Tacke,Philippe Christophe Breda,Annett Ostmann,Aaron Ochel

doi:10.1038/s41598-018-38432-3

Abstract

Immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN) are driven by inappropriately regulated cellular and humoral immune responses subsequently leading to renal tissue injury. Recent studies demonstrated the crucial role for regulatory T cells (Tregs) in suppressing pathogenic T-cell responses during nephrotoxic nephritis (NTN), a murine model of cGN. However, mechanisms of immune regulation in cGN are less clear. Here, we aim at investigating the role of the co-inhibitory PD-1/PD-L1 pathway in Treg-mediated suppression of renal inflammation. We demonstrated that Foxp3+ Tregs expressing PD-L1 infiltrate the kidney during NTN. Inhibition of PD-L1 signalling by using PD-L1−/− mice or by blockage of PD-L1 in wildtype mice resulted in an increased Treg frequency in the inflamed kidney. However, mice lacking PD-L1 developed more severe NTN associated with an elevated pathogenic renal Th1 immune response, which was reversed by blockage of IFNγ in these mice. Interestingly, lack of PD-L1 altered the gene expression profile of Tregs in homeostasis and kidney inflammation. Functionally, Tregs from nephritic PD-L1−/− mice had impaired suppressive capacity in vitro and failed to protect from NTN in vivo. Thus, PD-L1 displays a protective role in NTN, which is related to Treg-mediated suppression of the Th1 immune response.

Highlights

Crescentic glomerulonephritis is a severe glomerular disease characterized by formation of glomerular crescents in Bowman’s space and a rapid loss of renal function
We have shown recently that Tregs contribute to immune regulation in nephrotoxic nephritis (NTN), the murine model of crescentic glomerulonephritis (cGN), by inhibiting the pro-inflammatory Th1 immune response thereby ameliorating disease pathogenesis[20]
We showed an increased frequency of forkhead box protein P3 (Foxp3)+ Tregs in the inflamed kidneys of nephritic FIR-tiger mice compared to naive FIR-tiger mice (Fig. 1C, Supplemental Fig. 1A)

Summary

Introduction

Crescentic glomerulonephritis (cGN) is a severe glomerular disease characterized by formation of glomerular crescents in Bowman’s space and a rapid loss of renal function. The PD-l/PD-L1 pathway exerts important functions in immune regulation and promotes development and function of regulatory T cells (Tregs) by induction and maintenance of the Treg-specific transcription factor forkhead box protein P3 (Foxp3)[3]. The PD-1/PD-L1 pathway has been implicated in immune regulation of kidney diseases. Aged PD-1−/− mice were shown to develop lupus-like glomerulonephritis[9]. Kidney-infiltrating Th1 and Th17 cells were found to drive renal inflammation in murine models of cGN by production of the pro-inflammatory cytokines interferon-γ (IFNγ) and IL-17, respectively[15,16,17,18,19]. We have shown recently that Tregs contribute to immune regulation in nephrotoxic nephritis (NTN), the murine model of cGN, by inhibiting the pro-inflammatory Th1 immune response thereby ameliorating disease pathogenesis[20]. We investigated the immunoregulatory role of the co-inhibitory PD-1/PD-L1 pathway in Treg-mediated protection from renal injury

Methods

Results

Conclusion