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

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.

SUBMITTER: Neumann K

PROVIDER: S-EPMC6375967 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Neumann Katrin K Ostmann Annett A Breda Philippe Christophe PC Ochel Aaron A Tacke Frank F Paust Hans-Joachim HJ Panzer Ulf U Tiegs Gisa G

Scientific reports 20190214 1

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-inhibitor ...[more]

PMID: 30765734

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Project description:BackgroundFunction and efficiency of a transcription factor (TF) are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis (Crgn) where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto (WKY) strain.ResultsTo evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains (WKY and WKY.LCrgn2) that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD/Jun and JunD/ATF complexes (i.e., AP1 complex), which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide (LPS) stimulation we found that 2.4 fold more JunD/ATF-target genes were up-regulated as compared with JunD/Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response (P = 6.9 × 10⁻⁴) and antigen processing and presentation functions (P = 2.4 × 10⁻⁵), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF.ConclusionsIn summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis.

Project description:IntroductionCrescentic glomerulonephritis (CrGN) is a histologic feature of severe glomerular injury, clinically characterized by a rapid decline of renal function when not treated in a timely fashion. Factors associated with CrGN prognosis have not been thoroughly investigated. This study investigated the prognostic predictors of renal outcomes associated with CrGN, such as the histopathologic classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, arteriosclerosis, and tertiary lymphoid organ (TLO) formation.MethodsA total of 114 patients diagnosed with CrGN between 2010 and 2018 at two university-based hospitals has been retrospectively analyzed. Relationships between potential predictors and renal outcomes were analyzed using Cox proportional hazards model and linear regression analysis.ResultsThe mean age was 61.0 ± 15.3 years, and 49.1% were male. Among them, 92 (80.7%) and 11 (9.6%) patients were positive for ANCA and for anti-glomerular basement membrane antibody, respectively. During the median follow-up of 458.0 days, 55 patients (48.2%) had advanced to end-stage renal disease (ESRD). Cox proportional hazards analysis revealed that patients under the mixed and sclerotic classes had worse renal survival compared to those in the focal class (mixed: hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.18 to 11.82; P = 0.025; sclerotic: HR, 4.84; 95% CI, 1.44 to 16.32; P = 0.011). Severe arteriosclerosis was also associated with poor renal survival (HR, 2.44; 95% CI, 1.04 to 5.77; P = 0.042). TLOs were observed in 41 patients (36.0%). Moreover, TLO formation was also a prognostic factor for ESRD (HR, 1.82; 95% CI, 1.03 to 3.21; P = 0.040). In the multivariate linear regression analysis, age and sclerotic class were independent predictors for the change in estimated glomerular filtration rate during 1 year after biopsy.ConclusionsSpecific histopathologic findings, histopathologic classification, severity of arteriosclerosis, and TLO formation provide helpful information in predicting renal outcomes associated with CrGN.

Dataset Information

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

Publications

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

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