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:
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.
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
Krebs C, Schmidt T, Riedel J, Panzer U Nat Rev Nephrol. 2017 Oct
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
Krebs CF, Steinmetz OM.Mediators Inflamm. 2016
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
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