The suppressive effect of IL-17-expression in antigen specific CD8 T cells in acute experimental cholangitis in mice

Question:

Interleukin (IL)-17 has been associated with the pathogenesis of several autoimmune disorders. Increased numbers of Th 17 lymphocytes and IL-17 could be observed in serum and livers of patients with inflammatory liver diseases, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). We here investigate the role of IL-17 in disease induction using an inducible mouse model of acute cholangitis.

Methods:

K14-OVAp recipient mice express an ovalbumin peptide, the SIINFEKL sequence, on biliary epithelial cells. Acute cholangitis was induced by adoptive transfer of transgenic OVA-specific OT-1 CD8 T cells and OT-1 CD8 T cells lacking IL-17A/F to investigate the role of IL-17 in the initiation and progression of cholangitis. Liver enzymes, histology, cytokine expression and flow cytometry were used to assess liver inflammation.

Results:

Adoptive transfer of antigen specific OT-1 CD8 T cells led to portal inflammation in K14-OVAp recipient mice with the transferred cells mainly localized around bile ducts. The lack of IL-17A/F in transferred OT-1 CD8 T cells resulted in enhanced liver inflammation compared to the transfer of IL-17-competent OT-1 cells. Liver infiltrating antigen-specific CD8 T cells lacking IL-17 were highly activated, secreted large amounts of IFNγ and displayed increased proliferative capacity. Since biliary epithelial cells were activated after contact with CD8 T cells the increased accumulation of IL-17-deficient transferred OT-1 cells led to the enhanced expression of T cell directed chemokines with subsequent recruitment of endogenous T cells into the liver.

Conclusion:

We could here show that the lack of IL-17 in antigen specific CD8 T cells induces a severe phenotype of experimental cholangitis. Our results indicate an important suppressive function of IL-17 during the onset of antigen dependent cholangitis. Caution should be taken when targeting IL-17 for the treatment of cholangitis.