HEPATIC TOLERIZATION OF THE CD8+ T CELL IMMUNE RESPONSE

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DESCRIPTION (adapted from the application) The candidate has three years post-doctoral research experience, and will be shortly be completing his subspecialty training in hepatology and gastroenterology. This application for the mentored K08 award is submitted with the goal of providing the candidate with the further experience and training necessary to function as an independent investigator working in the field of liver immunology. The project's long-term objectives are to understand the mechanisms which result in sub-optimal T cell responses in the liver. This is a prerequisite for developing strategies to enhance the immune response against chronic infections of the liver including viral hepatitis B and C. We and others have demonstrated that in-vivo CD8+ T cell activation induced T cell death results in liver accumulation and apoptosis of CD8+ T cells. This lead to the hypothesis that the liver is a specific site for the removal of activated CD8+ T cells. The preliminary data demonstrates that activated CD8+ T cells flowing through the normal liver are retained by an ICAM-1 dependent mechanism (hepatic retention). The retained cells are in contact with liver macrophages (Kupffer cells), and a proportion undergo apoptosis after 14 hours of hepatic retention. The candidate proposes to; 1) Establish the proportion of activated CD8+ T cells that are undergoing apoptosis in the liver. II) Test the requirement for Kupffer cells during hepatic retention of CD8+ T cells. III) Determine if specific peptide in the liver results in division and apoptosis of activated CD8+ T cell. IV) Determine if intra-hepatic presentation of hepatocyte antigens by bone marrow derived cells results in CD8+ T cell priming or apoptosis. The Section of Immunobiology at Yale University is ideal for training because of the quality of the faculty, the breadth of their research, their experience as mentors and the core facilities at Yale. The School of Medicine has pledged protected time for the candidate during this training period prior to functioning as an independent investigator.