IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression

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...

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Published in:	Journal of hepatology 2021-04, Vol.74 (4), p.919-930
Main Authors:	Stein, Stephanie, Henze, Lara, Poch, Tobias, Carambia, Antonella, Krech, Till, Preti, Max, Schuran, Fenja Amrei, Reich, Maria, Keitel, Verena, Fiorotto, Romina, Strazzabosco, Mario, Fischer, Lutz, Li, Jun, Müller, Luisa Marie, Wagner, Jonas, Gagliani, Nicola, Herkel, Johannes, Schwinge, Dorothee, Schramm, Christoph
Format:	Article
Language:	eng
Subjects:	Adoptive transfer Animals Apoptosis Autoimmune diseases Autoimmune Diseases - immunology Autoimmune Diseases - pathology B7-H1 Antigen - metabolism Bile ducts Bile Ducts - immunology Biliary epithelial cell CD8 CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell death Cell proliferation Cholangitis Cholangitis - immunology Cholangitis - pathology Cytotoxicity Disease Models, Animal Gene Expression Regulation - physiology Humans Immune checkpoint Inflammation Inflammatory diseases Interleukin (IL)-17 Interleukin 17 Interleukin-17 - immunology Liver diseases Lymphocytes Lymphocytes T Major histocompatibility complex Medicin och hälsovetenskap Mice Mice, Transgenic Organoids Ovalbumin Ovalbumin - genetics PD-L1 protein Peptide Fragments - genetics Programmed cell death ligand 1 (PD-L1) Psoriasis
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Summary:	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. 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. 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. 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. 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. [Display omitted] •IL-17 induces the expression o
ISSN:	0168-8278 1600-0641 1600-0641