SFB1192

Project A2

Immune regulatory mechanisms of renal inflammation

Immune-mediated diseases such as crescentic glomerulonephritis (cGN) are driven by inappropriately regulated cellular and humoral immune responses subsequently leading to the development of renal failure. However, mechanisms of immune regulation in cGN are less clear. In a mouse model of cGN, we have shown previously that Foxp3+ regulatory T cells (Tregs) suppress the pathogenic T-cell response by production of IL-10. Recently, we demonstrated that the co-inhibitory PD-1/PD-L1 pathway promotes Treg function during cGN, which is crucial to control the inflammatory Th1 immune response. Interestingly, preliminary data suggest that also inflammatory CD8+ T-cell responses are regulated by the PD-1/PD-L1 pathway during cGN. However, the phenotype, pathogenic relevance, biological function, and regulation of renal CD8+ T-cell responses in cGN are still incompletely understood. Moreover, we identified proximal tubular epithelial cells (PTECs) as a population of non-professional antigen-presenting cells (APCs) in the kidney that, in contrast to non-professional APCs from the liver, induce immunity rather than tolerance. 

Thus, our studies will address the following aims:

1.) Phenotype and function of CD8+ T cells in murine models of acute and chronic kidney disease.

2.) Regulation of renal T-cell responses by targeting the co-inhibitory PD-1/PD-L1 pathway.

3.) Role of the co-inhibitory receptor TIGIT in the regulation of renal T-cell responses.

4.) Mechanisms of T-cell activation and regulation by non-professional APCs from kidney and liver.

5.) Phenotypic characterization of renal CD8+ T-cell subsets in cGN patients by single cell RNAseq and immunohistochemistry.

Our studies will result in a better understanding of mechanisms involved in the pathology and regulation of local inflammatory immune responses in acute and chronic kidney disease that may result in the identification of novel therapeutic targets in cGN.

Publication

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

    Neumann K, Ostmann A, Breda PC, Ochel A, Tacke F, Paust HJ, Panzer U, Tiegs G Sci Rep. 2019 Feb

  • IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN. 

    Diefenhardt P, Nosko A, Kluger MA, Richter JV, Wegscheid C, Kobayashi Y, Tiegs G, Huber S, Flavell RA, Stahl RAK, Steinmetz OMJ Am Soc Nephrol. 2018

  • RORγt expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses.

    Kluger MA, Nosko A, Ramcke T, Goerke B, Meyer MC, Wegscheid C, Luig M, Tiegs G, Stahl RA, Steinmetz OM.Clin Exp Immunol. 2017 Apr

  • T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN. 

    Nosko A, Kluger MA, Diefenhardt P, Melderis S, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OMJ Am Soc Nephrol. 2017 Jan

  • CXCR3+ regulatory T cells control Th1 responses in crescentic GN.

    Paust HJ, Riedel JH, Krebs CF, Turner JE, Brix SR, Krohn S, Velden J, Wiech T, Kaffke A, Peters A, Bennstein SB, Kapffer S, Meyer-Schwesinger C, Wegscheid C, Tiegs G, Thaiss F, Mittrücker HW, Steinmetz OM, Stahl RA, Panzer U.J Am Soc Nephrol. 2016 Jul

  • CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells.

    Evers BD, Engel DR, Böhner AM, Tittel AP, Krause TA, Heuser C, Garbi N, Kastenmüller W, Mack M, Tiegs G, Panzer U, Boor P, Ludwig-Portugall I, Kurts CJ Am Soc Nephrol. 2016 Nov

  • RORγt+Foxp3+ cells are an independent bifunctional regulatory T cell lineage and mediate crescentic GN.

    Kluger MA, Meyer MC, Nosko A, Goerke B, Luig M, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM.J Am Soc Nephrol. 2016 Feb

  • Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus.

    Kluger MA, Melderis S, Nosko A, Goerke B, Luig M, Meyer MC, Turner JE, Meyer-Schwesinger C, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM.Kidney Int. 2016 Jan

III. Medizinische Klinik und Poliklinik
Universitätsklinikum Hamburg-Eppendorf

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