ovalbumin and Cholangitis--Sclerosing

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.. 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.

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Movement; Cholangitis, Sclerosing; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Enterocytes; Liver; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Ovalbumin

The enterohepatic circuit of T cells may be responsible for the development of autoimmune liver disease. We employed transgenic mice to characterize phenotype and migration patterns of CD8 T cells activated in liver and gut.. We studied the migration of antigen-specific CD8 T cells primed in liver or gut after transfer in wild-type mice or mice that express ovalbumin in liver or gut. We performed transcriptome analysis of these two distinct T cell populations and confirmed our findings by flow cytometry.. Specific migration patterns were induced by activation of CD8 T cells in gut or liver. Gut-activated CD8 T cells expressed α4β7 and CCR9 and migrated to the gut and to the liver. Liver-activated T cells expressed integrins α4, α6, β1, α4β7 as well as CD62L, Ly6C, and neuropilin-1 and retained the capability to re-circulate through lymph nodes. Presence of the antigen increased retention of both types of activated T cells in the liver, but migration of liver-activated T cells to the gut was prohibited.. CD8 T cells primed in the liver in vivo are not capable of migrating to the gut, implying that the enterohepatic circuit of CD8 T cells is in fact a one-way road from the gut to the liver. Priming of CD8 T cells in the liver results in a distinct phenotype with attributes of central memory cells and induces a unique homing pattern. Gut-primed T cells preferentially home to the liver, in principle enabling them to induce autoimmune liver disease.

Topics: Animals; CD8-Positive T-Lymphocytes; Cell Movement; Cholangitis, Sclerosing; Disease Models, Animal; Enterohepatic Circulation; Hepatitis, Autoimmune; Intestines; Liver; Lymph Nodes; Mice, Inbred C57BL; Mice, Transgenic; Ovalbumin; Phenotype; Transcriptome