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（ILC 2，也称为天然辅助细胞或核细胞）与广泛的感染性和过敏性疾病密切相关。通过驻留在粘膜屏障并响应上皮来源的细胞因子如IL-33和IL-25，它们迅速释放早期2型细胞因子，其促进适应性CD 4 T细胞的Th 2炎症应答和B细胞的IgE产生。然而，ILC 2谱系的定义仍然是暂时的，在缺乏分子特征的情况下有些争议。此外，虽然它们与其他适应性和先天淋巴细胞一样来自相同的共同淋巴前体（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的基础上，该研究表明，先前被鉴定为天然样IL- 4/IL-13产生NKT细胞谱系的转录因子PLZF在ILC 2发育期间也以高水平表达。中心假设是PLZF在ILC 2的发育中发挥关键功能，并且PLZF-报告/删除小鼠可用于遗传跟踪和操纵ILC 2前体及其成熟后代。本申请的目的是使用PLZF-IRES-GFPCre小鼠鉴定ILC 2的骨髓前体，表征其分子程序，并在与ROSA 26-FL-STOP-FL-Tomato小鼠杂交后通过命运作图来确定其后代。此外，该项目将测试各种方法来在体内遗传操纵或消融ILC 2，作为表征其在生理学和过敏性气道炎症中功能的前奏。具体目标是：1）表征CLP的PLZFhi子集; 2）确定PLZF在ILC 2发育和功能中的作用; 3）创建ILC 2缺陷小鼠模型用于研究过敏性气道炎症。该项目具有创新性，因为它探索了PLZF表达在专门从事2型反应的先天和先天样谱系中共享的新想法，并且因为它将产生用于体内ILC 2研究的新模型和试剂。这将标志着我们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的能力发生重大转变。这项研究意义重大，因为它将大大提高我们对先天淋巴细胞谱系发育的理解。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组分的药剂成为可能。

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.