Dataset Information

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

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-1^wt or lacked IL-17A/F (OT-1^IL17ko). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro.

Results

Transfer of OVA-specific OT-1^IL17ko cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1^wt T cells. OT-1^IL17ko T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1^wt 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-1^IL17ko 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-1^wt 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.

SUBMITTER: Stein S

PROVIDER: S-EPMC8778963 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Stein Stephanie S Henze Lara L Poch Tobias T Carambia Antonella A Krech Till T Preti Max M Schuran Fenja Amrei FA Reich Maria M Keitel Verena V Fiorotto Romina R Strazzabosco Mario M Fischer Lutz L Li Jun J Müller Luisa Marie LM Wagner Jonas J Gagliani Nicola N Herkel Johannes J Schwinge Dorothee D Schramm Christoph C

Journal of hepatology 20201113 4

<h4>Background & aims</h4>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<sup>+</sup> T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.<h4>Methods</h4>K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on ...[more]

PMID: 33197512

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Dataset Information

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

Background & aims

Methods

Results

Conclusions

Lay summary

Publications

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

Similar Datasets

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