Analyzing the Heterogeneity of Innate Lymphoid Cells and the Relationship with their Microenvironments in situ and in vivo

分析先天淋巴细胞的异质性及其与原位和体内微环境的关系

• 批准号: 320406065
• 负责人: Professorin Dr. Anja Erika Hauser
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie (einschließlich Arbeitsbereich Physikalische Medizin)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320406065?language=en
• 关键词: Analyzing; Heterogeneity; Innate; Lymphoid; Cells

Innate lymphoid cells (ILCs) are thought to function as sensors within various organs in order to orchestrate tissue-specific immune responses. With cytokines as stimuli, ILCs are very sensitive tissue sensors during inflammatory processes, but also crucial for the maintenance of tissue homeostasis. ILCs develop in the bone marrow. Mature ILCs, grouped in ILC1-3 by their expression of key transcription factors and cytokines, are present throughout the body, and are especially enriched at barrier surfaces. However, different ILC subgroups show a clear tropism regarding certain tissues and organs. ILCs have initially been regarded to be a mainly tissue-resident immune cell population, however, these findings have been challenged recently. This raises the questions whether certain “niches” define the microenvironment of ILCs in various organs, to what extent these niches differ for ILC subgroups, whether the cellular and molecular characteristics of these niches change between homeostatic and inflammatory conditions, to what extent ILCs can adapt to “new” tissue microenvironments and which mechanisms apply for the attraction to and for the maintenance of the ILC subgroups in various tissues. In turn, all these questions call for an analysis of ILCs in situ, within their microenvironment. However, the fact that ILCs share many markers with other immune cells, especially T cells, in combination with their low abundance, has made histological analyses of these cells very difficult. In the previous funding period, we have established multi-epitope ligand cartography, which allows to stain for dozens of markers on one single tissue section, and combined this method with automated image analysis, which allows us to identify ILC subgroups and also developing ILCs in murine as well as human tissues. In the second funding period, we plan to analyze the localization, hematopoietic neighbour cells and the stromal microenvironment of developing and mature ILCs in the murine bone marrow of mice, to assess whether developing ILCs and various mature ILC subgroups occupy distinct cell-specific niches. These analyses will be extended to other tissues, in order to compare ILC niche composition on a cellular and molecular basis. We will compare the homeostatic situation to conditions of locally disturbed homeostasis, and analyze ILC dynamics by intravital microscopy. Furthermore, we will determine how tissue-specific microenvironments shape the phenotypic and functional characteristics of ILCs under systemic perturbations of homeostasis. Finally, we will translate our findings on ILC niche composition to human tissues, which we analyze by mutliplexed histology.

先天性淋巴样细胞（ILC）被认为是各种器官内的传感器，以协调组织特异性免疫反应。在细胞因子的刺激下，ILC在炎症过程中是非常敏感的组织传感器，而且对于维持组织稳态也至关重要。ILC在骨髓中发育。成熟的ILC通过其关键转录因子和细胞因子的表达而被分组为ILC 1 -3，其存在于整个身体中，并且尤其在屏障表面处富集。然而，不同的ILC亚组对某些组织和器官表现出明显的向性。ILC最初被认为是主要组织驻留的免疫细胞群体，然而，这些发现最近受到了挑战。这就提出了一些问题：某些“小生境”是否定义了各种器官中ILC的微环境，这些小生境在ILC亚组中的差异程度如何，这些小生境的细胞和分子特征是否在稳态和炎症条件之间发生变化，国际法委员会在多大程度上能够适应“新的”组织微环境以及哪些机制适用于吸引和维持各种组织中的ILC亚群。反过来，所有这些问题都要求在其微观环境中对国际劳工公司进行现场分析。然而，ILC与其他免疫细胞，特别是T细胞共享许多标志物的事实，以及它们的低丰度，使得这些细胞的组织学分析非常困难。在上一个资助期，我们已经建立了多表位配体制图，它允许在一个组织切片上染色数十个标记，并将这种方法与自动图像分析相结合，这使我们能够识别ILC亚组，并在小鼠和人类组织中开发ILC。在第二个资助期，我们计划分析小鼠骨髓中发育和成熟ILC的定位、造血相邻细胞和基质微环境，以评估发育中的ILC和各种成熟ILC亚组是否占据不同的细胞特异性小生境。这些分析将扩展到其他组织，以比较ILC生态位组成的细胞和分子的基础上。我们将比较稳态的情况下，局部扰动的稳态，并分析ILC动态活体显微镜。此外，我们将确定组织特异性微环境如何塑造ILC的表型和功能特征的系统扰动下的稳态。最后，我们将把我们的研究结果ILC生态位组成的人体组织，我们分析了多复合组织学。