Specific CD8+ T cell immunity in the murine liver

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The hepatic immune system is a critical interface between mucosal and systemic immunity. It promotes oral and systemic tolerance induction but can also support effective local immunity against pathogens (although hepatic T cell responses are prone to pathogenic dysregulations). Using established DNA- and protein-based vaccination protocols to prime B6 mice against different (HBV, SV40, OVA) antigens, we will define optimal conditions to (i) induce liver-homing anti-viral CTL responses; (ii) facilitate access of primed CTL to an antigen-bearing liver; and (iii) to establish a long-term, functional CTL memory in an antigen-bearing liver. Transgenic mouse lines that express transgene-encoded antigens in the liver will be used to facilitate studies of intrahepatic priming and restimulation of CD8+ T cells. Particular emphasis will be placed on the role of the hepatic innate immune system (NKT cells, NK cells, dendritic cells) in modulating the hepatic specific T cell system. The in vivo studies will be complemented by in vitro studies that will analyze the interaction of hepatic DC with NKT cells, NK cells and (CD4+ and CD8+) T cells. We will study the involvement of chemokines, the IL12/IL18/IFN pathway, the IFN/IL18 pathway, and TNF as well as LPS in supporting or eliminating an established T cell memory population in the liver. These preclinical investigations are considered of critical importance for the understanding and rational design of novel therapeutic approaches to the specific immunotherapy of chronic liver infections.