I类固有淋巴细胞发育分化的转录调控网络

In recent years, diverse innate lymphoid cell (ILC) subsets have been identified, which has extremely enriched the content of innate immunity and entirely redefined our classic maps of the immune system. In particular, newly identified group 1 ILCs (ILC1s) have evoked strong interest by many researchers. The term “ILC1” was coined on the basis of the findings of IFN-γ-producing ILCs at mucosal sites in humans and mice, but increasing evidence suggests that mucosal ILC1s and liver-resident NK cells, which has been described in our previous study for the first time, share a number of common characteristics in terms of phenotype, function and development. Although research into ILC1 development has been emerging, the transcriptional regulatory networks remain unclear. In this proposal, we will describe the expression profiling of transcription factors by ILC1 progenitor cells, explore the stages for the function of key transcription factors during ILC1 development, and clarify the cross-regulation among the key transcription factors, thereby clearly depicting ILC1 developmental pathway and serving as a paradigm for the study of other subsets in ILC family.

近年来，固有淋巴细胞（innate lymphoid cell, ILC）新亚群不断被揭示，极大地丰富了固有免疫的内涵，描绘免疫系统组成的传统图谱被重新改写。其中I类ILC（group 1 ILC, ILC1）新亚群的发现引起了学术界的广泛关注。ILC1概念的提出源于人和小鼠粘膜部位（扁桃体和肠道）的一群分泌IFN-γ的ILC，但越来越多证据提示粘膜ILC1与我们过去发现的肝脏驻留NK细胞在表型、功能和发育方面十分相似。尽管目前ILC1的发育分化已初见端倪，但其转录调控网络仍不清楚。本研究小组将揭示ILC1造血前体细胞的转录因子表达谱特性、探究关键转录因子在ILC1发育过程中发挥作用的时相、阐明关键转录因子之间的相互作用，从而描绘ILC1的发育分化路径，为ILC家族其他亚群的研究提供范例。

I类固有淋巴细胞（group 1 ILCs）是异质性的细胞群体，包含经典NK细胞、组织驻留NK细胞和粘膜ILC1s。本项目以我们前期发现的肝脏驻留NK细胞（也称为肝脏ILC1s）为关注对象，从转录调控角度揭示其与经典NK细胞、粘膜ILC1s的发育谱系关系，发现：(1) 肝脏驻留造血前体细胞高表达ILC1s相关转录因子T-bet 和PLZF；(2) T-bet促进肝脏前体细胞表达PLZF；(3) I类ILC亚群发育分化对T-bet和NFIL3的依赖程度不同；T-bet缺陷导致肝脏驻留NK细胞和粘膜ILC1s缺失，但仅影响部分经典NK细胞；NFIL3是 经典NK细胞发育分化高度依赖的转录因子，但存在部分NFIL3非依赖的肝脏驻留NK细胞和粘膜ILC1s；(4) 利用RORα条件敲除鼠，发现其缺失导致肝脏驻留NK细胞数量特异性减少，提示RORα对肝脏驻留NK细胞的稳态维持起重要作用。