SFB 1192

Project A5

Th17 cell plasticity in renal autoimmune disease

In the past, CD4+ T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, Th17 cells can have a high degree of plasticity and convert for example into pro-inflammatory Th1 cells or anti-inflammatory Tr1 cells. Interestingly, Th17 cells in experimental GN display limited spontaneous plasticity, as we have shown in this project. We furthermore introduced anti-CD3 injection as a tool to induce a regulatory phenotype in Th17 cells and trans-differentiation of Th17 cells into immunosuppressive IL-10-expressing Tr1 cells (Tr1exTh17 cells). Thus, targeting Th17 cell plasticity could be envisaged as a therapy in GN. However, the underlying mechanisms regulating stability and plasticity in Th17 cells are unclear to a large extent. To get insights into these mechanisms, we compared transcriptional profiles of stable renal and instable intestinal Th17 cells as well as of Tr1exTh17 cells obtained by bulk RNA-sequencing and single cell RNA-sequencing (scRNA-seq). On the basis of these data we aim now at uncovering the molecular basis for renal Th17 stability and at finding therapeutic targets for the modulation of the Th17 immune response. We will specifically address the following points: 1. Mechanisms of Th17 cell stability and plasticity (validation of specific candidates as identified in the first funding period (i.e. TCF-7, TOX, IL-27- receptor; in vivo CROP-seq for high-throughput screening of further potential candidates); 2. Environmental shaping of the Th17 immune response in the kidney compared to the intestine (interactome of Th17 cells and tissue cells; impact of human intestinal bacteria from ANCA-GN patients on Th17 cell plasticity and disease outcome in experimental models using patientspecific gnotobiotic mice). 3. Identification of developmental trajectories of human renal T cells by using the TCR as an endogenous barcode (TCR-sequencing and transcriptome analysis at the single cell level). Our long-term goal is to identify mechanisms shifting Th17 cells towards a regulatory phenotype that could be used as a therapeutic strategy in patients with glomerulonephritis in the future.

Publikationen

  • Drawing a single-cell landscape of the human kidney in (pseudo)-space and time.

    Krebs CF, Schlitzer A, Kurts C.Kidney Int. 2020 May

  • Single-Cell Transcriptomics Identifies the Adaptation of Scart1+ Vγ6+ T Cells to Skin Residency as Activated Effector Cells.

    Likai Tan, Inga Sandrock, Ivan Odak, Yuval Aizenbud, Anneke Wilharm, Joana Barros-Martins, Yaara Tabib, Alina Borchers, Tiago Amado, Lahiru Gangoda, Marco J. Herold, Marc Schmidt-Supprian, Jan Kisielow, Bruno Silva-Santos, Christian Koenecke, Avi-Hai Hovav, Christian Krebs, Immo Prinz, Sarina Ravens Cell Rep. 2019 Jun

  • Molecular and functional heterogeneity of IL-10-producing CD4+ T cells

    Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S, Bedke T, Ergen C, Manthey C, Agalioti T, Geffken M, Seiz O, Parigi S, Sorini C, Geginat J, Fujio K, Jacobs T, Roesch T, Izbicki J, Lohse A, Flavell R, Krebs C, Gustafsson J, Antonson P, Roncarolo M, Villablanca E, Gagliani N, Huber SNat Commun. 2018 Dec

  • T helper type 17 cells in immune-mediated glomerular disease

    Krebs C, Schmidt T, Riedel J, Panzer U Nat Rev Nephrol. 2017 Oct

  • IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo.

    Brockmann L, Gagliani N, Steglich B, Giannou AD, Kempski J, Pelczar P, Geffken M, Mfarrej B, Huber F, Herkel J, Wan YY, Esplugues E, Battaglia M, Krebs CF, Flavell RA, Huber S.J Immunol. 2017 Feb

  • CD4+ T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes.

    Krebs CF, Steinmetz OM.Mediators Inflamm. 2016

  • Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney. 

    Krebs CF, Paust HJ, Krohn S, Koyro T, Brix SR, Riedel JH, Bartsch P, Wiech T, Meyer-Schwesinger C, Huang J, Fischer N, Busch P, Mittrücker HW, Steinhoff U, Stockinger B, Perez LG, Wenzel UO, Janneck M, Steinmetz OM, Gagliani N, Stahl RA, Huber S, Turner JE, Panzer U.Immunity. 2016 Nov

  • Plasticity of Th17 Cells in Autoimmune Kidney Diseases. 

    Krebs CF, Turner JE, Paust HJ, Kapffer S, Koyro T, Krohn S, Ufer F, Friese MA, Flavell RA, Stockinger B, Steinmetz OM, Stahl RA, Huber S, Panzer UJ Immunol. 2016 Jul

III. Medizinische Klinik und Poliklinik
Universitätsklinikum Hamburg-Eppendorf

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