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.
CD4+ T cells produce GM-CSF and drive immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12.
Hans-Joachim Paust, Ning Song, Donatella De Feo, Nariaki Asada, Selma Tuzlak, Yu Zhao, Jan-Hendrik Riedel, Malte Hellmig, Amirrtavarshni Sivayoganathan, Anett Peters, Anna Kaffke, Alina Borchers, Ulrich O Wenzel, Oliver M Steinmetz, Gisa Tiegs, Elisabeth Meister, Matthias Mack, Christian Kurts, Sibylle von Vietinghoff, Maja T Lindenmeyer, Elion Hoxha, Rolf A K Stahl, Tobias B Huber, Stefan Bonn, Catherine Meyer-Schwesinger, Thorsten Wiech, Jan-Eric Turner, Burkhard Becher, Christian F Krebs, Ulf PanzerSci Transl Med. 2023 Mar
Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection.
Bartsch P, Kilian C, Hellmig M, Paust HJ, Borchers A, Sivayoganathan V, Enk L, Zhao Y, Shaikh N, Büttner H, Wong MN, Puelles VG, Wiech T, Flavell R, Huber TB, Turner JE, Bonn S, Huber H, Gagliani N, Mittrücker HW, Rohde H, Panzer U, Krebs CF.PLoS Pathog. 2022 Apr
Tissue-specific therapy in immune-mediated kidney diseases: new ARGuments for targeting the IL-23/IL-17 axis.
Krebs CF, Tuner JE, Riedel JH, Panzer UJ Clin Invest. 2021 Jun
Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients
Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N, Krebs CF Sci Immunol. 2021 Feb
Pathogen-induced tissue-resident memory TH17 (TRM17) cells amplify autoimmune kidney disease.
Krebs CF, Reimers D, Zhao Y, Paust HJ, Bartsch P, Nuñez S, Rosemblatt MV, Hellmig M, Kilian C, Borchers A, Enk LUB, Zinke M, Becker M, Schmid J, Klinge S, Wong MN, Puelles VG, Schmidt C, Bertram T, Stumpf N, Hoxha E, Meyer-Schwesinger C, Lindenmeyer MT, Cohen CD, Rink M, Kurts C, Franzenburg S, Koch-Nolte F, Turner JE, Riedel JH, Huber S, Gagliani N, Huber TB, Wiech T, Rohde H, Bono MR, Bonn S, Panzer U, Mittrücker HW.Sci Immunol. 2020 Aug
TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer.
Laura Garcia Perez, Jan Kempski, Heather M McGee, Penelope Pelzcar, Theodora Agalioti, Anastasios Giannou, Leonie Konczalla, Leonie Brockmann, Ramez Wahib, Hao Xu, Maria Carolina Amezcua Vesely, Shiwa Soukou, Babett Steglich, Tanja Bedke, Carolin Manthey, Oliver Seiz, Björn-Philipp Diercks, Stylianos Gnafakis, Andreas H Guse, Daniel Perez, Jakob R Izbicki, Nicola Gagliani, Richard A Flavell, Samuel HuberNat Commun. 2020 May
Molecular and functional heterogeneity of IL-10-producing CD4+ T cells.
Leonie Brockmann, Shiwa Soukou, Babett Steglich, Paulo Czarnewski, Lilan Zhao, Sandra Wende, Tanja Bedke, Can Ergen, Carolin Manthey, Theodora Agalioti, Maria Geffken, Oliver Seiz, Sara M Parigi, Chiara Sorini, Jens Geginat, Keishi Fujio, Thomas Jacobs, Thomas Roesch, Jacob R Izbicki, Ansgar W Lohse, Richard A Flavell, Christian Krebs, Jan-Ake Gustafsson, Per Antonson, Maria Grazia Roncarolo, Eduardo J Villablanca, Nicola Gagliani, Samuel HuberNat Commun. 2018 Dec
Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney.
Christian F Krebs, Hans-Joachim Paust, Sonja Krohn, Tobias Koyro, Silke R Brix, Jan-Hendrik Riedel, Patricia Bartsch, Thorsten Wiech, Catherine Meyer-Schwesinger, Jiabin Huang, Nicole Fischer, Philipp Busch, Hans-Willi Mittrücker, Ulrich Steinhoff, Brigitta Stockinger, Laura Garcia Perez , Ulrich O Wenzel, Matthias Janneck, Oliver M Steinmetz, Nicola Gagliani, Rolf A K Stahl, Samuel Huber, Jan-Eric Turner, Ulf PanzerImmunity. 2016 Nov
A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease.
Penelope Pelczar, Mario Witkowski, Laura Garcia Perez, Jan Kempski, Anna G Hammel, Leonie Brockmann, Dörte Kleinschmidt, Sandra Wende, Cathleen Haueis, Tanja Bedke, Marco Witkowski, Susanne Krasemann, Stefan Steurer, Carmen J Booth, Philipp Busch, Alexandra König, Ursula Rauch, Daniel Benten, Jakob R Izbicki, Thomas Rösch, Ansgar W Lohse, Till Strowig, Nicola Gagliani, Richard A Flavell, Samuel HuberScience. 2016 Oct
Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation
Nicola Gagliani, Maria Carolina Amezcua Vesely, Andrea Iseppon, Leonie Brockmann, Hao Xu, Noah W Palm, Marcel R de Zoete, Paula Licona-Limón, Ricardo S Paiva, Travers Ching, Casey Weaver, Xiaoyuan Zi, Xinghua Pan, Rong Fan, Lana X Garmire, Matthew J Cotton, Yotam Drier, Bradley Bernstein, Jens Geginat, Brigitta Stockinger, Enric Esplugues, Samuel Huber, Richard A Flavell Nature. 2015 Jul