Tilman Schmidt1, Jonas Luebbe1,2, Christoph Kilian1,2, Jan-Hendrik Riedel1,2, Sonja Hiekmann1,2, Nariaki Asada1,2, Pauline Ginsberg1,2, Lennart Robben1,2, Ning Song2,3, Anna Kaffke1,2, Anett Peters1,2, Alina Borchers1,2, Richard A Flavell4,5, Nicola Gagliani6,7,8,9, Penelope Pelzcar6,7, Samuel Huber6,7, Tobias B Huber1,7, Jan-Eric Turner1,7, Hans-Joachim Paust1,2, Christian F Krebs1,2,7, Ulf Panzer10,2,7. 1. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Division of Translational Immunology, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China. 4. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut. 5. Howard Hughes Medical Institute, Yale University, New Haven, Connecticut. 6. I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 7. Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 9. Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden. 10. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany panzer@uke.de.
Abstract
BACKGROUND: IL-17A-producing CD4+ T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4+ T cell subsets, remains to be elucidated. METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4+CD45RBhigh T cell transfer colitis model. RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4+ T cells and, most importantly, specifically in CD4+ TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4+ TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.
BACKGROUND: IL-17A-producing CD4+ T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4+ T cell subsets, remains to be elucidated. METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4+CD45RBhigh T cell transfer colitis model. RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4+ T cells and, most importantly, specifically in CD4+ TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4+ TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.
Authors: Erik M Disteldorf; Christian F Krebs; Hans-Joachim Paust; Jan-Eric Turner; Geraldine Nouailles; André Tittel; Catherine Meyer-Schwesinger; Gesa Stege; Silke Brix; Joachim Velden; Thorsten Wiech; Udo Helmchen; Oliver M Steinmetz; Anett Peters; Sabrina B Bennstein; Anna Kaffke; Chrystel Llanto; Sergio A Lira; Hans-Willi Mittrücker; Rolf A K Stahl; Christian Kurts; Stefan H E Kaufmann; Ulf Panzer Journal: J Am Soc Nephrol Date: 2014-06-05 Impact factor: 10.121
Authors: Hans-Joachim Paust; Jan-Eric Turner; Jan-Hendrik Riedel; Erik Disteldorf; Anett Peters; Tilman Schmidt; Christian Krebs; Joachim Velden; Hans-Willi Mittrücker; Oliver M Steinmetz; Rolf A K Stahl; Ulf Panzer Journal: Kidney Int Date: 2012-04-11 Impact factor: 10.612
Authors: A R Kitching; S R Holdsworth; V A Ploplis; E F Plow; D Collen; P Carmeliet; P G Tipping Journal: J Exp Med Date: 1997-03-03 Impact factor: 14.307