肝窦内皮细胞（LSEC）诱导特异性T细胞产生耐受，在维持肝脏免疫耐受中发挥重要作用。迄今尚不清楚，机体通过何种机制逆转LSEC的致耐作用而清除肝内HBV。文献报道：NK细胞可通过调控抗原提呈细胞功能而增强特异性CTL应答。我们前期研究也发现：模式识别受体NOD1信号通路可以LSEC依赖性方式增强T细胞应答；NK细胞在肝内募集、活化及分泌TNF-α，可促进LSEC活化，其机制有待阐明。申报者推测：HBV感染过程中，NK细胞可诱导LSEC活化表型表达，并与HBV感染转归相关。为此，本项目拟借助NK-LSEC孵育体系、抗体阻断或基因敲除小鼠、HBV感染动物模型、乙肝患者肝组织标本，开展如下研究：①探讨NK细胞对LSEC表型的调控作用，及其对肝内CTL应答的影响；②通过阻断和激活相关分子，调控LSEC表面共刺激分子/共抑制分子间平衡。本项目可望为探寻防治慢性HBV感染的新策略提供理论依据和新靶点。

Liver sinusoidal endothelial cells (LSEC) play an important role in maintaining immune tolerance by induction of specific T cells inability. It is still unclear how to reverse the tolerogenic effect of LSEC and mediate the clearance of HBV. It has been reported that natural killer cells (NK cells) could enhance virus specific cytotoxic T lymphocyte response through activation of antigen presenting cells. Our previous studies also indicated that activation of Pattern recognition receptor (for example NOD1) signaling in the liver could enhance T cell response in a LSEC dependent manner. The recruitment and activation of NK cells in the liver and the following TNF-α secretion facilitated the activation of LSEC, the mechanisms involved need to be clarified. Our hypothesis is that NK cells could induce the activation phenotype of LSEC, which are associated with the outcome of HBV infection. In this study, we will use NK-LSEC co-culture system, neutralization antibody, gene knockout mice, HBV infection animal model, as well as blood and liver sample of chronic hepatitis B patient to determine activating effect of NK cells on LSEC and intrahepatic CTL responses and to explore its mechanisms. Besides, we try to regulate the balance between co-stimulatory molecules and co-inhibitory molecules of LSEC by blocking or stimulating associated molecules, which may activate CTL responses and control HBV infection. Our study will be helpful to provide theoretical basis and novel targets for the development of new anti-HBV immunotherapies.