Highlights
- •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.
Methods
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.
Results
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.
Conclusion
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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 14, 2019
Accepted:
May 21,
2019
Received in revised form:
May 20,
2019
Received:
September 28,
2018
See Editorial, pages 657–659Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
