Stephanie Stein1, Lara Henze1, Tobias Poch1, Antonella Carambia1, Till Krech2, Max Preti1, Fenja Amrei Schuran1, Maria Reich3, Verena Keitel3, Romina Fiorotto4, Mario Strazzabosco4, Lutz Fischer5, Jun Li5, Luisa Marie Müller6, Jonas Wagner7, Nicola Gagliani8, Johannes Herkel1, Dorothee Schwinge9, Christoph Schramm10. 1. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany. 4. Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. 5. Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Leibniz Institute for Experimental Virology, Heinrich Pette Institute, Hamburg, Germany. 7. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 9. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: d.schwinge@uke.de. 10. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: cschramm@uke.de.
Abstract
BACKGROUND & AIMS: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8+ T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids. METHODS: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8+ T cells that either had OT-1wt or lacked IL-17A/F (OT-1IL17ko). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro. RESULTS: Transfer of OVA-specific OT-1IL17ko cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1wt T cells. OT-1IL17ko T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1wt CD8+ T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1IL17ko T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8+ T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1wt T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes. CONCLUSIONS: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8+ T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis. LAY SUMMARY: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
BACKGROUND & AIMS: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8+ T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids. METHODS: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8+ T cells that either had OT-1wt or lacked IL-17A/F (OT-1IL17ko). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro. RESULTS: Transfer of OVA-specific OT-1IL17ko cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1wt T cells. OT-1IL17ko T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1wt CD8+ T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1IL17ko T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8+ T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1wt T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes. CONCLUSIONS: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8+ T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis. LAY SUMMARY: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
Authors: Michal Marzec; Qian Zhang; Ami Goradia; Puthiyaveettil N Raghunath; Xiaobin Liu; Michele Paessler; Hong Yi Wang; Maria Wysocka; Mangeng Cheng; Bruce A Ruggeri; Mariusz A Wasik Journal: Proc Natl Acad Sci U S A Date: 2008-12-16 Impact factor: 11.205
Authors: Ruth Y Z Lan; Thucydides L Salunga; Koichi Tsuneyama; Zhe-Xiong Lian; Guo-Xiang Yang; Willy Hsu; Yuki Moritoki; Aftab A Ansari; Claudia Kemper; Jeff Price; John P Atkinson; Ross L Coppel; M Eric Gershwin Journal: J Autoimmun Date: 2008-12-19 Impact factor: 7.094
Authors: G J Freeman; A J Long; Y Iwai; K Bourque; T Chernova; H Nishimura; L J Fitz; N Malenkovich; T Okazaki; M C Byrne; H F Horton; L Fouser; L Carter; V Ling; M R Bowman; B M Carreno; M Collins; C R Wood; T Honjo Journal: J Exp Med Date: 2000-10-02 Impact factor: 14.307
Authors: Ye Htun Oo; Vanessa Banz; Dean Kavanagh; Evaggelia Liaskou; David R Withers; Elizabeth Humphreys; Gary M Reynolds; Laura Lee-Turner; Neena Kalia; Stefan G Hubscher; Paul Klenerman; Bertus Eksteen; David H Adams Journal: J Hepatol Date: 2012-07-14 Impact factor: 25.083