CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice

Hepatology. 2014 Feb;59(2):601-11. doi: 10.1002/hep.26702. Epub 2013 Dec 18.


The pathogenesis of primary sclerosing cholangitis (PSC) remains poorly understood. Since PSC predominantly occurs in patients with inflammatory bowel disease, autoimmunity triggered by activated T cells migrating from the gut to the liver is a possible mechanism. We hypothesized that T cells primed in the gut-associated lymphoid tissue (GALT) by a specific antigen migrate to the liver and cause cholangitis when they recognize the same antigen on cholangiocytes. We induced ovalbumin-dependent colitis in mice that express ovalbumin in biliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that express ovalbumin in enterocytes (iFABP-OVA mice). We analyzed T-cell activation in the GALT and crossreactivity to the same antigen in the liver as well as the effects of colitis per se on antigen-presentation and T-cell activation in the liver. Intrarectal application of ovalbumin followed by transfer of CD8 OT-I T cells led to antigen-dependent colitis. CD8 T cells primed in the GALT acquired effector function and the capability to migrate to the liver, where they caused cholangitis in a strictly antigen-dependent manner. Likewise, cholangitis developed in mice expressing ovalbumin simultaneously in biliary epithelia and enterocytes after transfer of OT-I T cells. Dextran sodium sulfate colitis led to increased levels of inflammatory cytokines in the portal venous blood, induced activation of resident liver dendritic cells, and promoted the induction of T-cell-dependent cholangitis.

Conclusion: Our data strengthen the notion that immune-mediated cholangitis is caused by T cells primed in the GALT and provide the first link between colitis and cholangitis in an antigen-dependent mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Movement
  • Cholangitis, Sclerosing / immunology*
  • Cholangitis, Sclerosing / pathology*
  • Cholangitis, Sclerosing / physiopathology
  • Colitis / chemically induced
  • Colitis / metabolism
  • Colitis / pathology
  • Cytokines / metabolism
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Enterocytes / metabolism
  • Enterocytes / pathology
  • Liver / pathology
  • Lymphoid Tissue / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Ovalbumin / metabolism


  • Cytokines
  • Ovalbumin
  • Dextran Sulfate