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.
