Transcriptional Control of Group 1 Innate Lymphoid Cells

先天性淋巴样细胞（inate lymphoid cells，ILC）是近年来发现的一种异质性淋巴细胞，在淋巴器官形成、机体免疫应答和组织内环境稳定等方面发挥重要作用。关于T辅助细胞，ILC可以分为三组：i）第1组ILC产生IFNg并且依赖于转录因子T-bet、Eomes和/或RORgt，ii）第2组ILC产生白细胞介素（IL）-5和IL-13并且依赖于转录因子加塔-3和ROR α，和iii）第3组ILC，其产生IL-17和IL-22，依赖于转录因子RORgt。到目前为止，已经在第1组ILC中检测到两种不同的谱系; i）表达T-bet和Eomes的常规NK细胞，和ii）最初从第3组ILC发育但在其分化期间松散RORgt（Ex-RORgt）同时维持T-bet表达的细胞。为了阐明是否存在第1组ILC的额外谱系，我们已经建立了报告小鼠品系，其使得我们能够鉴定同一小鼠内的经典NK细胞和Ex-RORgt第1组ILC。对这些小鼠的分析显示，存在第三群第1组ILC，主要存在于肠的固有层和肠系膜淋巴结中。我们现在想彻底检查这个新鉴定的第1组ILC群体的发育、功能和转录控制，并将其与其他第1组ILC群体（即NK细胞和Ex-RORgt ILC）进行比较。ILC行使多种功能的事实使其成为药物干预的有趣目标。拟议的研究旨在确定不同的第1组ILC内独特的信号通路和功能特性。从长远来看，这将有助于药物的设计，将干扰特定的第1组ILC。

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.