Allergic inflammation in genetic models of lung ILC2 deficiency

描述（由申请人提供）：先天2型淋巴细胞（ILC2，也称为自然辅助细胞或营养细胞）在广泛的感染性和过敏性疾病中起重要作用。通过驻留在粘膜屏障上并响应上皮源性细胞因子如IL-33和IL-25，它们迅速释放早期2型细胞因子，促进适应性CD4 T细胞的Th2炎症反应和B细胞的IgE产生。然而，在缺乏分子特征的情况下，ILC2谱系的定义仍然是暂定的，并且有些争议。此外，尽管它们起源于与其他适应性和先天淋巴细胞相同的共同淋巴样前体（CLP），但它们的发育中间体及其与其他相关谱系的关系尚不清楚。该项目建立在我们实验室生产的PLZF- ires - gfpcre报告小鼠的初步研究基础上，表明转录因子PLZF，先前被认为是先天样IL- 4/IL-13产生NKT细胞谱系的标志，在ILC2s的发育过程中也高水平表达。核心假设是PLZF在ILC2s的发育中发挥关键作用，PLZF-报告/删除小鼠可用于遗传跟踪和操纵ILC2前体及其成熟后代。本应用程序的目的是使用PLZF-IRES-GFPCre小鼠鉴定ILC2的骨髓前体，表征其分子程序，并通过与ROSA26-FL-STOP-FL-Tomato小鼠杂交后的命运定位来确定其后代。此外，该项目将测试各种方法，通过基因操作或在体内切除ILC2，作为表征其在生理学和过敏性气道炎症中的功能的前奏。具体目标是：1)表征CLP的PLZFhi子集；2)确定PLZF在ILC2发育和功能中的作用；3)建立ilc2缺陷小鼠模型用于变应性气道炎症的研究。该项目具有创新性，因为它探索了PLZF表达在先天和先天样谱系中共享的新观点，专门从事2型反应，因为它将为体内ILC2s的研究提供新的模型和试剂。这将标志着我们在理解和进一步操纵先天免疫在由2型免疫引起或治愈的全球疾病中的作用方面的能力发生重大转变。提出的研究是重要的，因为它将大大提高我们对先天淋巴细胞谱系发育的理解。所开发的概念和工具将使开发针对寄生虫和过敏原的先天免疫的不同成分的药物成为可能。

DESCRIPTION (provided by applicant): Innate type 2 lymphocytes (ILC2, also called natural helper cells or nuocytes) are critically involved in widespread infectious and allergic diseases. By residing at mucosal barriers and responding to epithelial-derived cytokines such as IL-33 and IL-25, they rapidly release the early type 2 cytokines that promote the Th2 inflammatory responses of adaptive CD4 T cells and the IgE production of B cells. However, the definition of the ILC2 lineage remains tentative and somewhat controversial in the absence of molecular signature. Furthermore, while they derive from the same common lymphoid precursors (CLP) as other adaptive and innate lymphocytes, their developmental intermediates and their relationship with other related lineages are unknown. This project builds on preliminary studies of PLZF-IRES-GFPCre reporter mice produced in our laboratory showing that the transcription factor PLZF, previously identified as the signature of the innate-like IL- 4/IL-13-producing NKT cell lineage, is also expressed at high levels during the development of ILC2s. The central hypothesis is that PLZF exerts critical functions in the development of ILC2s and that PLZF- reporter/deleter mice can be used to genetically track and manipulate ILC2 precursors and their mature progeny. The objective of this application is to use PLZF-IRES-GFPCre mice to identify the bone marrow precursors of ILC2, characterize their molecular program and define their progeny through fate mapping after crossing to ROSA26-FL-STOP-FL-Tomato mice. Furthermore, the project will test various approaches to genetically manipulate or ablate ILC2 in vivo as a prelude to characterizing their function in physiology and in allergic airway inflammation. The specific aims are: 1) to characterize the PLZFhi subset of CLP; 2) to determine the role of PLZF in ILC2 development and function; 3) to create ILC2-defective mouse models for studies of allergic airway inflammation. The project is innovative because it explores the novel idea that PLZF expression is shared across innate and innate-like lineages specializing in type 2 responses and because it will produce new models and reagents for studies of ILC2s in vivo. This would signal a major shift in our ability to understand and further manipulate the role of innate immunity in worldwide diseases caused or cured by type 2 immunity. The proposed research is significant because it will considerably enhance our understanding of innate lymphocyte lineage development. The concepts and tools developed will make it possible to develop agents that target distinct components of innate immunity to parasites and allergens.