Transcriptional Control of Group 1 Innate Lymphoid Cells

先天淋巴样细胞（Innate lymphoid cells, ILCs）是近年来发现的一种异质性淋巴细胞群，在淋巴器官形成、抗微生物免疫反应和组织稳态中发挥重要作用。参照辅助T细胞，ILCs可分为三组：i) 1组ILCs产生IFNg，依赖于转录因子T-bet、Eomes和/或RORgt； ii) 2组ILCs产生IL -5和IL-13，依赖于转录因子GATA-3和rorα； iii) 3组ILCs产生IL-17和IL-22，依赖于转录因子RORgt。到目前为止，在1组ILCs中发现了两个不同的谱系；i)表达T-bet和Eomes的常规NK细胞；ii)最初由3组ILCs发育而在分化过程中丢失RORgt的细胞（前RORgt），同时保持T-bet的表达。为了澄清是否存在额外的1组ILCs谱系，我们建立了一个报告小鼠品系，使我们能够在同一只小鼠中识别经典NK细胞和Ex-RORgt 1组ILCs。对这些小鼠的分析显示，存在第三种1组ILCs，主要存在于肠道固有层和肠系膜淋巴结。我们现在想要从发育、功能和转录控制方面彻底检查这个新发现的1组ILC群体，并将其与其他1组ILC群体（即NK细胞和Ex-RORgt ILC）进行比较。事实上，ILCs具有多种功能，使其成为药物干预的有趣目标。提出的研究旨在确定不同1组ilc中独特的信号通路和功能特性。从长远来看，这将有助于设计干扰特定1组ilc的药物。

Innate lymphoid cells (ILCs) form a recently discovered heterogeneous group of lymphocytes, which play an important role in lymphorganogenesis, the immune response against microorganisms and tissue homeostasis. In reference to T helper cells ILCs can be divided into three groups: i) group 1 ILCs produce IFNg and are dependent on the transcription factors T-bet, Eomes and/or RORgt, ii) group 2 ILCs produce Interleukin (IL)-5 and IL-13 and are dependent on the transcription factors GATA-3 and RORalpha, and iii) group 3 ILCs, which produce IL-17 and IL-22, depend on the transcription factor RORgt. So far two distinct lineages have been detected withihn group 1 ILCs; i) conventional NK cells that express T-bet and Eomes and ii) cells which originally develop from group 3 ILCs but loose RORgt during their differentiation (Ex-RORgt) while maintaining T-bet expression. To clarify whether there is an additional lineage of group 1 ILCs, we have established a reporter mouse strain, which enables to us to identify classical NK cells and Ex-RORgt group 1 ILCs within the same mouse. Analysis of these mice revealed that there is a third population of group 1 ILCs, primarily present in the lamina propria of the gut and the mesenteric lymph nodes. We now want to thoroughly examine this newly identified population of group 1 ILCs with respect to development, function and transcriptional control and compare it with the other group 1 ILC populations (i.e. NK cells and Ex-RORgt ILCs). The fact that ILCs exercise manifold functions makes them an interesting target for pharmaceutical intervention. The proposed study aims at identifying unique signalling pathways and functional properties within different group 1 ILCs. In the long term this will be instrumental for the design of drugs that will interfere with specific group 1 ILCs.