细胞毒性T淋巴细胞（CTL）功能缺陷或耗竭是导致HBV持续性感染的重要因素之一，其机制尚未完全阐明。肝窦内皮细胞（LSEC）和库否细胞（KC）在调控肝内CTL活化中发挥了重要作用。申请人前期研究发现，HBV感染会导致 LSEC和KC调控CTL活化的能力出现差异分化，TLR2信号途径在此过程中发挥重要作用。据此推测，LSEC和KC通过TLR2识别HBV所含PAMP启动的信号转导改变了各自免疫分化状态，进而调控肝内CTL活化并影响疾病转归。本项目拟借助HBV动物模型和临床乙肝患者标本，研究TLR2信号途径在HBV诱导LSEC和KC免疫功能差异分化中的作用，阐明LSEC和KC差异调控肝内病毒特异性CTL活化的分子机制及对疾病转归的影响。本项目将有助于进一步阐明肝内HBV特异性CTL应答的调控机制，为探索更有效阻断HBV持续性感染的免疫干预策略提供理论基础和实验依据。

Persistent HBV infection is associated with functional exhaustion of virus-specific cytotoxic T lymphocytes (CTL). However, the mechanism of such T cell dysfunction is so far unclear. As the local antigen presenting cells, liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC) play an important role in regulating CTL activation in the liver. In our previous studies, we found that HBV infection modulates the immune regulating function of LSEC and KC with TLR2 signaling pathways involving. Therefore, we hypothesize that LSEC and KC recognize HBV PAMP through TLR2, which leads to altered differentiation of CTL regulating functions of the cells. The differentiation status of LSEC and KC determines the CTL activation in liver and thus influences the outcome of HBV infection. By using HBV infection animal models and clinical samples of HBV patients, we will further study the role of TLR2 signaling pathways in HBV inducing functional differentiation of LSEC and KC. We will also characterize the molecular mechanism of LSEC and KC regulating HBV specific CTL activation and its impact on the outcome of disease. The results of this study will contribute to elucidating liver specific mechanisms of regulating CTL response against hepatitis virus infection, and will provide theoretical and experimental evidences for designing new immunotherapy strategies for chronic hepatitis B.