肝脏特有NK细胞的肝内发育分化途径及其分子调控机制

The natural killing (NK) cell pool consists of heterogenous subpopulations, and current studies on NK cells are mainly focused on their natural defenses against tumors and virus-infected cells. Our paper recently published in J Clin Invest described a liver-resident NK cell subset (accouting for nearly 50% of total hepatic NK cells) for the first time. Substantial differences existed between liver-resident NK cells and conventional NK cells; the former exhibited the CD49a+DX5- phenotype, pocessed memory characteristics and regulatory functions, and possibly originated from the liver. Given that adult liver retains hematopoietic potential, we wonder whether there is an intrahepatic pathway for liver- resident NK cell development. By comparison to the intra-bone marrow pathway for conventianl NK cell development, we will search for hematopoietic stem/progenitor cells (HSPCs) in the liver and the precursors of liver-resident NK cells, identify key transcription factors controlling the development and differentiation of liver-resident NK cell precursors, and verify intrahepatic cytokines or ligands determining the development, differentiation or residence of liver-resident NK cells. By performing the proposed research, we will take the lead in understanding the characteristics of liver-resident NK cell development and extend our former knowledge about the fundamental biological features of NK cells.

自然杀伤（NK）细胞是异质性的细胞群体，目前主要研究其对肿瘤和病毒感染细胞的"自然杀伤"特性。我们近期发表于J Clin Invest的研究工作首次揭示了一群肝脏特有NK细胞（占肝脏NK细胞约50%），具有CD49a+DX5-的独特表型，有记忆和调节功能，可能发生发育于肝脏本身，显示出与经典NK 细胞的诸多差异。鉴于成年肝脏具有骨髓外造血功能（即可能部分保留胚胎肝脏的造血功能），为进一步了解肝脏特有NK细胞是否存在肝脏内的独立发育分化路径，本项目将以经典NK细胞的骨髓发育分化路径为参照，寻找肝脏造血干/祖细胞（HSPCs）和肝脏特有NK细胞的前体细胞，鉴定影响肝脏特有NK细胞的前体细胞发育分化的关键转录因子，发现肝脏微环境中影响肝脏特有NK细胞发育、分化、驻留的关键细胞因子或配体，得以率先了解肝脏特有NK细胞的发育分化特性，扩展对NK细胞基本生物学特性的认识，继续占领该研究领域的高地。

自然杀伤（NK）细胞是异质性的细胞群体，目前主要研究其对肿瘤和病毒感染细胞的“自然杀伤”特性。我们近期发表于J Clin Invest的研究工作首次揭示了一群肝脏特有NK细胞，即肝脏驻留NK细胞，占肝脏NK细胞约50%，具有CD49a+DX5-的独特表型，有记忆和调节功能，可能发生发育于肝脏本身，显示出与经典NK 细胞的诸多差异。鉴于成年肝脏具有骨髓外造血功能（即可能部分保留胚胎肝脏的造血功能），为进一步了解肝脏特有NK细胞是否存在肝脏内的独立发育分化路径，本项目以经典NK细胞的骨髓发育分化路径为参照，寻找肝脏造血干/祖细胞（HSPCs）和肝脏特有NK细胞的前体细胞，我们发现了具有造血干细胞特征的成年肝脏Lin-Sca-1+Mac-1+前体细胞起源于胚胎肝脏；发现肝脏NK 前体（NKP）相对其他脏器NKP高表达CD49a，且肝脏CD49a+ NKP在体内具有定向发育成肝脏特有CD49a+DX5- NK细胞的潜能；发现T-bet是内源性影响肝脏特有NK细胞及其前体发育分化的关键转录因子；发现IFN-γ信号特异性影响肝脏特有NK细胞发育，而对经典NK细胞无影响。上述研究结果使我们得以率先了解肝脏特有NK细胞的发育分化特性，扩展对NK细胞基本生物学特性的认识，继续占领该研究领域的高地。