组织微环境对人NK细胞程序性分化增殖的影响

Natural killer cells have been considered a heterogeneous population and may be divided into different subsets. We also characterized four novel populations defined by CD56, CD11b and CD27, which can represent the distinct stages of human NK cells from different tissues. Furthermore, we demonstrated that each population could be characterized by unique functional and phenotypic attributes. However, many new questions have arisen from our research. For example, which specific microenvironment elements allow for NK cells to locate in different tissue or organs? Can inflammatory cytokines trigger programmed differentiation and proliferation of NK cell during homeostasis and following infection? How transcription factors can directly modulate NK cell function and their pathogenic contribution to human diseases? Based on our extensive preliminary findings, we will indicate the programmed proliferation of NK cell after exposure to microenvironment elements. We will: 1) test a number of different cytokine combinations for their ability to support the proliferation and differentiation of human CD34+ hematopoietic stem cells (HSCs) into different NK cell populations; 2) test the hypothesis that inflammatory cytokines polarize the function of NK cell within solid organs in physiological and pathological microenvironment and 3) Further identify the specific transcription factors for the control of NK cell development and functions. It is to be hoped that research results in our understanding of the developmentally programmed and microenvironmentally driven functions of NK populations; particularly their cytokines production and transcriptional regulation, which shape the tissue microenvironment and contribute to host protection and tissue inflammation.

NK细胞有多种亚群，我们也利用 CD11b和CD27等分子将人NK细胞分为表型和功能不同的四个亚群。但随着研究的深入也出现新的科学问题：哪些微环境因素趋化NK细胞进入并定居在不同的组织或器官？哪些炎性因子在生理或病理状态时触发NK细胞的程序性分化和增殖？哪些转录因子直接调控NK细胞的功能及其与疾病的相关性？为了回答上述问题，我们将在前期工作的基础上进一步揭示微环境因素介导的NK细胞程序性增殖现象：1）分析体外环境中不同细胞因子组合促进CD34+造血干细胞分化为不同亚群NK细胞；2）分析组织生理和病理微环境中不同炎性因子组合促进未成熟NK细胞极化为不同功能NK细胞；3）进一步鉴定NK细胞在发育分化和功能极化过程中特异性转录因子的调控作用。籍此探明NK细胞的发育进程，特别是发生在微环境中的细胞因子诱导的、转录因子介导的NK细胞程序性增殖现象，从而弄清NK细胞在宿主防御和组织损伤中的双面角色。

组织微环境对NK细胞程序性发育分化、功能极化和转录调控的机制尚不清楚，本课题揭示微环境因素介导NK细胞程序性增殖分化及调控机制：1）建立体外环境中不同细胞因子组合促进CD34+造血干细胞分化为不同亚群NK细胞：发现IL-15促进CD49a+ Eomes- NK细胞的诱导分化，与肝脏组织居留NK细胞表型相似，IL-4促进CD49a+ Eomes+ NK细胞的诱导分化，与子宫组织居留NK细胞表型和功能相似；2）发现TGF-b介导肺癌病理微环境NK细胞代谢失常功能丧失：肿瘤微环境累积大量 TGF-b，促进NK细胞上调表达 FBP1，异常表达的 FBP1 抑制细胞自身糖酵解代谢，同时破坏细胞存活能力，最终导致 NK 细胞功能紊乱，抑制 NK 细胞的 FBP1 活性，能够恢复 NK 细胞功能；3）发现转录因子PBX1调控NK细胞发育分化：鉴定PBX1是NK细胞高度保守的转录因子，在NK细胞中PBX1可以直接分别结合生长促进因子PTN和OGN启动子区调控其转录，PBX1-PTN/OGN轴上调T-bet表达促进骨髓NK细胞终末成熟，参与体内成熟NK细胞库的形成和维持。该研究不仅对于深入理解NK细胞的发育和成熟具有重要意义，而且对于进一步完善基于NK细胞过继转输的免疫治疗方案也有深远影响。