SFB 1192

Project A5

Th17 cell plasticity in renal autoimmune disease

T cells play a pivotal role in the pathogenesis in various autoimmune diseases, by their ability to differentiate into pathogenic effector Th1 and Th17 cells or protective regulatory T cells (Treg). This includes human and experimental glomerulonephritis. Classically, these CD4+ T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. Recent data suggests that CD4+ T cells and Th17 cells in particular have a high degree of plasticity in the brain and intestine, where Th17 can produce IFN-γ and transdifferentiate into Th1 cells. In addition, we found that Th17 cells can also upregulate IL-10 and acquire a regulatory phenotype. We therefore aimed to study Th17 cell plasticity in kidney diseases.

Unexpectedly, we found in adoptive transfer experiments and in fate reporter mice that TH17 cells have very limited spontaneous plasticity in the kidney of nephritic mice. However, we were able to promote a regulatory phenotype of Th17 cells (rTh17) in the kidney using CD3-specific antibody treatment. The mechanisms that control stability and transdifferentiation of TH17 cells towards TH1 or regulatory T cells are incompletely understood.
In this project we therefore aim to study Th17 cell plasticity in experimental crescentic GN (nephrotoxic nephritis, NTN) and in a model of lupus nephritis (Pristane).

We will address the following points:

  1. Identification of factors that contribute to the stability of renal Th17 cells.
  2. Analysis of mechanisms inducing regulatory Th17 cells in GN during tolerance induction by anti-CD3 treatment with a focus on the role of IL-10 and TGF-β1. 
  3. Analysis of human renal T cells for markers of cell plasticity by flow cytometry.

Our long-term goal is to identify mechanisms for a shift of Th17 cells towards a regulatory phenotype that could be used as a therapeutic strategy in GN patients in the future.

 

Publikationen

  • 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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