免疫微环境对肝脏驻留NK细胞稳态维持及其机制研究

Natural killer (NK) cells are central components of the innate immune system. Recent studies have revealed that the heterogeneity of NK cells is related to their tissue distribution. Our research published in 2013 has for the first time reported that the liver contains a NK cell subset with unique phenotypic and functional properties (accouting for about 50% of total liver NK cells), which is termed ‘liver-resident NK cells’ and is currently categorized into a new innate lymphoid cell (ILC) subset. The finding of liver-resident NK cells marked the beginning of study of tissue-specific NK cells. Within the last two years, remarkable progress has been made in the development and transcriptional regulation of liver-resident NK cell lineage. However, influence of tissue-microenvironmental factors on the homeostasis of liver NK cell subsets remains unknown. This proposal will search for the key cell types and molecules within hepatic microenvironment regulate the homeostasis of liver-resident NK cells, and study the roles of different cell types and functional molecules in liver-resident NK cell development, function and maintenance, thereby providing firsthand information on the generation of liver-resident NK cells and shedding new light on the regulation of tissue-specific NK cells by the local niche.

自然杀伤（NK）细胞是固有免疫系统核心成员，近来研究证实NK细胞存在异质性并与组织分布密切相关。我们于2013年在国际上率先揭示成年肝脏存在一群表型和功能独特的NK细胞亚群（占肝脏总NK细胞约50%），称为肝脏驻留NK细胞（Liver-resident NK cells），同时被学界列为新一类固有淋巴细胞（ILC）类型，拉开了组织器官特有NK细胞研究的序幕。近两年有关肝脏驻留NK细胞谱系发育的转录调控取得了一系列突破性进展，然而肝脏免疫微环境对肝脏驻留NK细胞稳态的维持及其机制几乎为空白。本项目拟系统寻找免疫微环境中调控肝脏驻留NK细胞命运和稳态的核心细胞和关键分子，分析肝脏不同类型细胞及其功能分子在肝脏驻留NK细胞发育分化、功能成熟以及稳态维持中的作用，为全面描述肝脏驻留NK细胞的形成机制提供第一手资料，同时为阐明其它组织器官特有NK细胞的稳态维持提供新研究视角。

肝脏NK细胞是异质性的群体，其中组织驻留NK细胞占据较高比例。尽管近年围绕肝脏驻留（liver-resident NK，LrNK）NK细胞的转录调控研究取得一定进展，但免疫微环境对LrNK细胞发育分化和稳态维持的影响尚不清楚。本项目发现：（1）IFN-γ信号缺失导致LrNK细胞减少，但不影响其增殖和凋亡；IFN-γ受体在肝脏造血前体细胞上高表达，这些造血前体细胞具有LrNK细胞发育潜能，IFN-γ信号通过促进肝脏造血前体细胞增殖，维持LrNK细胞的数量；（2）在接触性超敏反应模型中，半抗原致敏诱导LrNK细胞IL-7Rα表达上调，记忆性LrNK细胞集中在表达IL-7Rα的细胞群体中，通过体内阻断IL-7Rα，发现IL-7受体信号对于记忆性LrNK细胞的长期维持具有关键作用；（3）发现CD8 T细胞促进不成熟的CD27+ LrNK向成熟的CD27- LrNK细胞分化，而阻断CD8 T细胞表面CD27的配体—CD70分子，则可逆转该过程；揭示CD8 T细胞通过表面CD70与LrNK细胞表面CD27相互作用，促进LrNK细胞成熟。