Abstract: TH-OR065

The Co-Inhibitory Molecule PD-L1 Contributes to Regulatory T Cell-Mediated Protection in Murine Crescentic Glomerulonephritis

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Neumann, Katrin, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Ostmann, Annett, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Breda, Philippe Christophe, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Paust, Hans-Joachim, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Panzer, Ulf, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Tiegs, Gisa, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background

Glomerular diseases such as crescentic glomerulonephritis (cGN) are mediated by inappropriate cellular and humoral immune responses towards autoantigens subsequently leading to the development of end-stage renal failure. Previously, we demonstrated a crucial role for regulatory T cells (Tregs) in suppressing pro-inflammatory Th1 and Th17 cell-mediated immune responses during nephrotoxic nephritis (NTN), the murine model of cGN. However, mechanisms of immune regulation in cGN are insufficiently understood. Here, we aim at investigating the role of the co-inhibitory molecule PD-L1 in Treg-mediated protection from NTN.

Methods

NTN was induced in PD-L1-/- mice by injection of the nephritogenic serum. Disease severity was investigated at day 8 after NTN induction and compared to C57BL/6 wild type (WT) mice. Kidney damage was quantified by crescent formation in PAS-stained tissue sections and determination of albumin-to-creatinine ratio by ELISA. PD-L1 was blocked in WT mice by injection of an anti-PD-L1 antibody. To neutralize IFNγ, PD-L1-/- mice were treated with an anti-IFNγ antibody. Tregs from nephritic PD-L1-/- or WT mice were adoptively transferred into Rag1-/- mice one day before NTN induction. Gene and protein expression analysis was done by quantitative RT-PCR and flow cytometry.

Results

PD-L1-/- mice developed more severe NTN compared to WT mice. Histological analysis revealed increased numbers of T cells, macrophages/DCs but also Foxp3+ Tregs in the kidneys of nephritic PD-L1-/- mice. Moreover, renal and systemic IFNγ-mediated Th1 immune response as well as systemic humoral immune response were strongly enhanced in nephritic PD-L1-/- mice. Blockage of PD-L1 in WT mice amplified renal Th1 response and aggravated disease pathogenesis. Furthermore, neutralization of IFNγ ameliorated NTN in PD-L1-/- mice. In co-culture, renal DCs from nephritic PD-L1-/- mice strengthened expression of IFNγ in CD4+ T cells. Interestingly, PD-L1-/- Tregs were not able to suppress activation and proliferation of responder CD4+ T cells in vitro and they also failed to protect from NTN in vivo.

Conclusion

PD-L1 displays a protective role in NTN, which is related to Treg- and DC-dependent suppression of the Th1 immune response. Thus, targeting PD-L1 may represent a novel therapeutic option in cGN.