title: CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, CVK, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seidel
authors.forename: Ira
authors.initials: I
authors.lastname: Eickmeier
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Eckart
authors.initials: E
authors.lastname: Schott
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D002465:Cell Movement; D015209:Cholangitis, Sclerosing / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010047:Ovalbumin / Q000378:metabolism
chemical_list: D016207:Cytokines; D010047:Ovalbumin; D016264:Dextran Sulfate