人类肝脏特有NK细胞的发现及其基本特性研究

Recently, our lab discovered a murine liver-resident NK cell population (liver-NK), occupying around 50% of total liver NK cells, with an unique phenotype of DX5-CD49a+, which is opposite to conventional NK cells (DX5+CD49a-).This liver-NK cell dose not develop from bone marrow and not move from blood circulation but origins inside liver, suggesting there are two types of NK cells in liver, and providing a chance to re-consider the roles of NK cells in liver immune tolerance and related liver diseases. In this study, we will at first time figure out the general characteristics of human liver NK cells by phenotyping and molecularly featuring human NK cells within livers from a pilot of human fresh normal livers (more than 50 samples); meanwhile, our study will provide evidences to support our hypothesis “liver: an organ with predominant innate immunity” existing not only in mice but also in human by examining all innate immune cells including NK, MAIT, γζT and ILCs within normal liver; we will also demonstrate the distribution of human functional NK subsets and differential intermediates; importantly, we will explore if there is human liver-NK cell (CD56+CD49+) within human livers and confirm its preliminary function. Based on the study from normal liver, we will extensively compare human NK cells from normal livers with those from patients with HBV infection or HCC, in order to understand the pathologic role of NK cells or liver-NK cells or NK subsets in human liver diseases. This is a basic and pioneer study, directly unveiling of NK cell’s role in human liver diseases.

最近我们实验室首次报道了一群小鼠肝脏特有NK细胞，占肝脏总NK细胞约50%，细胞表型为独特的DX5-CD49a+，由肝内独立发育而不是通过血液循环而来，提示肝脏有二套独立的NK细胞系统，为研究NK细胞与肝脏免疫耐受及相关肝病提供全新视角。本研究拟通过较大群体（50例以上）的人类肝脏新鲜标本库进行肝脏NK细胞总体描述，获取第一套人类肝脏NK细胞的免疫表型、分子群谱等标准数据（描绘“概貌图”），以确认肝脏高含NK细胞的基本事实，并揭示肝脏NK细胞各亚群的分布和可能的发育分化路径；同时深入验证人类肝脏是否存在类似小鼠的肝脏特有NK细胞（CD56+CD49+ NK细胞）并广泛鉴定其免疫表型和功能特性；在此基础上，将研究乙型肝炎和肝癌病人中肝脏特有NK细胞的免疫病理学意义。本研究是人体肝脏免疫学研究领域的基础性、前沿性工作，将使人类更好理解NK细胞在各种肝脏疾病的生理学和病理学意义。

最近我们实验室首次发现一群小鼠肝脏特有的DX5-CD49a+NK细胞亚群，为研究NK细胞与肝脏免疫耐受及相关肝病提供了全新视角。本项目课题通过大量人类肝脏新鲜标本，进行人类肝脏NK细胞的基本特性研究，为人类肝脏NK细胞进行全面标准的概貌性描述，验证发现人类肝脏中也含有一群类似小鼠的人类肝脏特有的NK细胞亚群，并比对人类肝脏特有NK细胞亚群和经典NK细胞亚群的分子群谱差异，为人类特有NK细胞分子指纹和基本属性进行概貌描述。在此基础上，本项目继续研究乙型肝炎相关肝癌病人的肝脏组织中NK细胞病理状态和免疫特性改变，发现在肝癌病人肝脏中不仅肝脏特有NK细胞数量显著增加，而且还伴随NK细胞免疫功能的耗竭，并发现CD96和NKG2A这两个NK细胞受体可以准确预测肝癌病人的预后和NK细胞的预存免疫力，采用抗体阻断CD96和NKG2A后可以有效的恢复NK细胞杀伤肿瘤的能力，提示靶向CD96和NKG2A逆转肝脏免疫逃逸具有潜在应用前景。本研究不仅对正常人体肝脏NK细胞进行了基础性概貌描述，而且还对人类NK细胞在肝脏疾病的病理特性进行了探索，具有理论意义和临床转化前景。