T cell mediated cholangitis alters bile acid metabolism

Background and Aims:

It is becoming increasingly clear that lipid metabolites such as bile acids affect lymphocyte function. It is unknown whether lymphocytes in turn are able to regulate bile acid metabolism. Both mechanisms could contribute to cholestatic liver inflammation. We therefore aimed to investigate the effect of T cells causing antigen dependent cholangitis on bile acid metabolism in a newly developed mouse model of cholangitis.

Methods:

Mdr2ko mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2xK14-OVAp). Antigen dependent T cell damage was induced by the adoptive transfer of T cell receptor transgenic OT-1 CD8 positive T cells. Bile acid metabolism was assessed by quantification of bile acids in liver and serum using a targeted liquid chromatography – mass spectrometry based approach and by analyzing the expression of rate limiting enzymes and bile acid transporters.

Results:

Transfer of antigen specific CD8 positive T cells into Mdr2xK14-OVAp mice led to a significant increase in serum ALT levels and severe peribiliary inflammation. Liver infiltrating T cells produced increased levels of the proinflammatory cytokines IFN gamma and TNF alpha. T cell mediated cholangitis resulted in significantly increased levels of total conjugated bile acids in serum and livers of recipient mice, whereas unconjugated bile acid levels were reduced. In the liver, T cell transfer led to a significant downregulation of genes responsible for bile acid synthesis and uptake and an increased expression of the bile salt export pump. CD8 positive T cells alone were able to induce these changes, as demonstrated in Mdr2xK14-OVAp recipient mice on the RAG1knockout background. This effect was at least in part mediated by TNF.

Conclusion:

By using a novel mouse model which combines antigen dependent T cell and bile acid induced liver injury, we demonstrate that CD8 positive T cell suffice to significantly downregulate bile acid metabolism. Understanding this interplay may have implications for designing combined treatment strategies for cholestatic liver diseases.