Kupffer cell mediated deletion of activated CD8+ T cells

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DESCRIPTION (provided by applicant): The immune response in the liver is frequently sub-optimal. Clinical examples of this are infection with hepatitis B and C viruses, as well as tolerance to oral and alloantigens. We are interested in the fate of activated CD8+ T cells after they have entered the liver and have demonstrated that i) the liver retains activated CD8+ T cells that enter it, even in the absence of specific peptide ii) the retained cells are in physical contact with Kupffer ceils (KC) and iii) undergo apoptosis. Between events i and iii very little is known about the retained CD8+ T cells. In the preliminary data generated in the first two years of the KO8 award we show that a) activated CD8+ T cells on entering the liver undergo approximately seven fold expansion over 48 hours b) this is followed by a gradual decrease over the next 5 days due to intrahepatic apoptosis c) the presence of specific peptide results in significant reduction in the retained CD8+ T cell pool due to enhanced apoptosis d) in the absence of KC, specific peptide does not results in reduction in the activated CD8+ T cell population. These results demonstrate that KC are required for antigen induced deletion of intrahepatic activated CD8+ T cells, and are consistent with two hypothesis: Hypothesis A: Antigen presentation by KC is responsible for antigen induced deletion of intraheptic CD8+ T cells. Hypothesis B: Antigen presentation on non-KC is responsible for antigen induced deletion of intrahepatic CD8+ T cells, but KC have an important role in delivering the apoptotic signal. Specific aim 1: Determine if KC specific inhibition of class I MHC processing in-vivo blocks apoptosis of intrahepatic CD8+ T cells. Specific aims 2a) Determine if antigen presentation by KC to activated CD8+ T cells in-vitro results in CD8+ T cell apoptosis. 2b) Determine if Kupffer cell ICAM-1, CD95-L, indoleamine dioxygenase and galectin-1 are important in the firm adhesion and apoptosis of CD8+ T cells. These aims will be achieved by using transgenic mice in which MHC class I presentation is inhibited in KC, and by developing in-vitro systems in which the role of the molecules in specific aim 2b in KC mediated apoptosis is tested.