Specific CD8+ T cell immunity in the murine liver

肝脏免疫系统是粘膜和全身免疫之间的关键接口。它促进口服和全身耐受诱导，但也可以支持对病原体的有效局部免疫（尽管肝T细胞反应容易发生致病性失调）。利用已建立的基于DNA和蛋白质的疫苗接种方案，让B6小鼠接种不同的（HBV, SV40， OVA）抗原，我们将确定最佳条件，以(i)诱导肝脏归巢的抗病毒CTL反应；（ii）促进引物CTL进入携带抗原的肝脏；（iii）在携带抗原的肝脏中建立长期的功能性CTL记忆。在肝脏中表达转基因编码抗原的转基因小鼠系将用于促进肝内启动和再刺激CD8+ T细胞的研究。特别强调肝脏先天免疫系统（NKT细胞，NK细胞，树突状细胞）在调节肝脏特异性T细胞系统中的作用。体内研究将辅以体外研究，分析肝DC与NKT细胞、NK细胞和（CD4+和CD8+） T细胞的相互作用。我们将研究趋化因子、il - 12/ il - 18/IFN通路、IFN/ il - 18通路、TNF以及LPS在支持或消除肝脏中已建立的T细胞记忆群中的作用。这些临床前研究被认为对理解和合理设计慢性肝脏感染特异性免疫治疗的新治疗方法至关重要。

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.