Subproject A10

Primary sclerosing cholangitis (PSC) is an extraintestinal manifestation of inflammatory bowel disease. Its pathogenesis is unclear. The phenotype of liver infiltrating T-cells in PSC argues for activation of these cells in the intestine and subsequent migration to the liver.
During the last funding period we have investigated the migration patterns of antigen-specific CD8 T-cells activated in the intestine or in the liver. An accumulation of T-cells in the liver was observed, which was amplified when the antigen was present in the liver. In the next funding period, T-cells activated in intestine or liver or cells that migrated to the liver after activation in the intestine will be characterized by gene array analysis. We aim at identifying candidate molecules responsible for the recruitment of activated T-cells to the liver.
During the last funding period we have developed an animal model, in which T-cells activated in the intestine during antigen-specific colitis (OVA-colitis) migrate to the liver and cause cholangitis, which depends on the expression of the same antigen in the bile ducts under the apical sodium-dependent bile transporter promoter (ASBT-OVA mice). Thereby, we have for the first time developed an animal model, in which the enterohepatic circuit of T-cells causes cholangitis. This model will be further characterized in the next funding period, especially regarding potential therapeutic interventions.
Naive CD8 T-cells transferred into TF-OVA mice, which express the antigen ovalbumin in hepatocytes under the transferrin-promoter, are activated and develop effector function. We demonstrated previously that bone-marrow dependent APCs are required for their activation. In the next funding period we aim at identifying the APC population responsible for their activation or induction of tolerance. Transfer of naive CD8 T-cells into TF-OVA mice leads to transient hepatitis, which is suppressed by endogenous regulatory T-cells. We will investigate which APC population is required for the induction of regulatory T-cells in the liver. To this end we will deplete Kupffer cells or dendritic cells in TF-OVA mice before transfer of CD8 T-cells. We will further generate bone-marrow chimeras using major histocompatibility complex-I (MHC-I) deficient bone marrow or hosts.  
The phenotype of liver-derived regulatory T-cells and their ability to suppress cholangitis or colitis will be tested in the OVA-colitis model. The investigation of regulatory cells will also be carried out in TF-OVA mice crossed to Depletion of Regulatory T-cell (DEREG) mice.