Research Article| Volume 71, ISSUE 4, P783-792, October 2019

Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis


      • Antigen-specific CD8+ T cells can control bile acid metabolism in a murine model of cholangitis.
      • The effect of T cells on bile acid metabolism partly depends on TNF and IFN-γ, and on T cell contact with hepatocytes.
      • Understanding the effect of lymphocytes on bile acid metabolism may help in the design of combined treatment strategies.

      Background & Aims

      T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BAs) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis.


      Mdr2−/− mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2−/−xK14-OVAp). T cell-mediated cholangitis was induced by the adoptive transfer of antigen-specific CD8+ T cells. BA levels were quantified using a targeted liquid chromatography-mass spectrometry-based approach.


      T cell-induced cholangitis resulted in reduced levels of unconjugated BAs in the liver and significantly increased serum and hepatic levels of conjugated BAs. Genes responsible for BA synthesis and uptake were downregulated and expression of the bile salt export pump was increased. The transferred antigen-specific CD8+ T cells alone were able to induce these changes, as demonstrated using Mdr2−/−xK14-OVAp recipient mice on the Rag1−/− background. Mechanistically, we showed by depletion experiments that alterations in BA metabolism were partly mediated by the proinflammatory cytokines TNF and IFN-γ in an FXR-dependent manner, a process that in vitro required cell contact between T cells and hepatocytes.


      Whereas it is known that BA metabolism is dysregulated in sepsis and related conditions, we have shown that T cells are able to control the synthesis and metabolism of BAs, a process which depends on TNF and IFN-γ. Understanding the effect of lymphocytes on BA metabolism will help in the design of combined treatment strategies for cholestatic liver diseases.

      Lay summary

      Dysregulation of bile acid metabolism and T cells can contribute to the development of cholangiopathies. Before targeting T cells for the treatment of cholangiopathies, it should be determined whether they exert protective effects on bile acid metabolism. Herein, we demonstrate that T cell-induced cholangitis resulted in decreased levels of harmful unconjugated bile acids. T cells were able to directly control synthesis and metabolism of bile acids, a process which was dependent on the proinflammatory cytokines TNF and IFN-γ. Understanding the effect of lymphocytes on bile acid metabolism will help in the design of combined treatment strategies for cholestatic liver diseases.

      Graphical abstract


      Linked Article

      • Bile acid metabolism and T cell responses in cholangiopathy: Not one-way traffic
        Journal of HepatologyVol. 71Issue 4
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          Cholangiocytes, also termed biliary epithelial cells, make a vital contribution to liver physiology and in maintaining homeostasis within the liver microenvironment.1 They line the biliary tree and play a central role in regulating bile composition through the secretion of water, electrolytes and solutes via the expression of a range of membrane transporters. Additionally, they are involved in cross talk with other cellular populations (both resident and non-resident) and through major internal cellular pathways, such as senescence, apoptosis/proliferation, they maintain tissue homeostasis.
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