Immune regulatory mechanisms of renal inflammation
Immune-mediated diseases, such as crescentic glomerulonephritis (cGN), are driven by inappropriately regulated cellular and humoral immune responses leading to renal injury and decline in kidney function. 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. Thus, our studies will address the following aims: 1.) Phenotype and function of CD8+ T cells in murine models of acute and chronic cGN. 2.) Regulation of inflammatory T cell responses by the co-inhibitory receptors PD-1 and TIGIT. 3.) Mechanisms of T cell activation and regulation by non-professional APCs from kidney and liver. 4.) 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 cGN that may result in the identification of novel therapeutic targets in cGN.
Transcriptional and Clonal Characterization of Cytotoxic T cells in Crescentic Glomerulonephritis.
Anne Mueller, Yu Zhao, Hakan Cicek, Hans-Joachim Paust, Amirrtavarshni Sivayoganathan, Alexandra Linke, Claudia Wegscheid, Thorsten Wiech, Tobias B Huber, Catherine Meyer-Schwesinger, Stefan Bonn, Immo Prinz, Ulf Panzer, Gisa Tiegs, Christian F Krebs, Katrin NeumannAm Soc Nephrol. 2023 Mar
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
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
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
Stat3 programs Th17-specific regulatory T cells to control GN.
Kluger MA, Luig M, Wegscheid C, Goerke B, Paust HJ, Brix SR, Yan I, Mittrücker HW, Hagl B, Renner ED, Tiegs G, Wiech T, Stahl RAK, Panzer U, Steinmetz OM.J Am Soc Nephrol. 2014 Jun