The Origin and Role of Pulmonary ILC2 Subsets in Anti-Helminth Immunity

项目摘要 世界卫生组织估计，土壤传播的蠕虫感染全球四分之一的人。 保护或清除这些寄生蠕虫需要启动2型免疫反应。生产性 2型免疫和蠕虫清除依赖于三种关键的细胞因子：白细胞介素（IL）-4，IL-5和IL-13。 第2组先天性淋巴样细胞（ILC 2）是2型细胞因子的重要来源。具体而言，ILC 2细胞 感觉受损粘膜并作为早期协同抗蠕虫免疫。目前，我国大部分 关于ILC 2细胞在抗蠕虫免疫中的作用的理解源于集中于组织的工作， 驻留ILC 2或天然ILC 2（nILC 2）细胞。然而，我们和其他人最近描述了第二个子集， 迁移性ILC 2，称为炎性ILC 2（iILC 2）细胞。不同的表型、时间、起源和功能 这些不同的ILC 2亚群的差异表明iILC 2细胞在抗蠕虫免疫中起独特的作用。 本文概述的研究将解决我们知识中的以下关键空白：1） iILC 2细胞，这仍在争论中。2)iILC 2细胞如何转运到肺以及它们进入肺的程度 感染期间的软组织是未知的。3)iILC 2细胞对组织驻留ILC 2群体的影响 目前尚不清楚，它们在长期保护免受蠕虫感染方面的作用尚未得到探讨。下面的目标 将通过测试中心假设来解决这些知识空白，即迁移性iILC 2细胞，起源于 小肠或骨髓前体，在进入肺后获得nILC 2表型，并有助于 对屏障免疫有显著影响。目的1：确定iILC 2来源和组织 寄生虫感染的异质性。目的2：阐明iILC 2迁移和渗出到细胞内的机制。 肺目的3：确定在连续的免疫后iILC 2细胞对组织驻留ILC 2池的贡献程度。 N. brasiliensis暴露这些目标在概念上都是创新的（通过挑战当前的教条 周围的iILC 2细胞）和方法（通过使用独特的报告小鼠和基因组系统来跟踪命运， iILC 2细胞的功能）。这一建议是重要的，因为了解iILC 2细胞的起源，如何 它们排出并迁移到发炎的粘膜，以及它们对长期组织驻留ILC 2的贡献。 肺中的ILC 2群体显著推进了我们对ILC 2生物学的理解。填补这些关键空白， 这些知识将确立iILC 2细胞作为蠕虫感染的关键第一反应者的作用， 确定有助于其在长期屏障维护和完整性方面发挥作用的机制。

Project Summary The World Health Organization estimates that soil transmitted helminths infect 1 in 4 people worldwide. Protection or clearance of these parasitic worms requires the initiation of a type-2 immune response. Productive type-2 immunity and worm clearance are dependent on three key cytokines: interleukin (IL)-4, IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2) represent an important source of type-2 cytokines. Specifically, ILC2 cells sense damaged mucosa and act as early orchestrators anti-helminth immunity. Currently, much of our understanding regarding the role of ILC2 cells in anti-helminth immunity stems from work focused on tissue- resident ILC2 or natural ILC2 (nILC2) cells. However, we and others have recently described a second subset of migratory ILC2s, termed inflammatory ILC2, (iILC2) cells. The distinct phenotype, timing, origin, and function of these distinct ILC2 subsets suggests that iILC2 cells serve a unique role in anti-helminth immunity. The studies outlined herein will address the following critical gaps in our knowledge: 1) The origin(s) of iILC2 cells, which remains in debate. 2) How iILC2 cells transit to the lung and the extent they enter the parenchyma during infection is unknown. 3) The impact that iILC2 cells have on tissue-resident ILC2 population remains unclear, and their role in long-term protection against helminths has not been explored. The aims below will address these knowledge gaps by testing the central hypothesis that migratory iILC2 cells, originating from small intestine or bone marrow precursors, acquire an nILC2 phenotype upon entry into the lung and contribute significantly to barrier immunity after repeated helminth infection. Aim 1: Determine iILC2 origin and tissue heterogeneity during helminth infection. Aim 2: Elucidate the mechanism of iILC2 migration and diapedesis into the lung. Aim 3: Determine the extent that iILC2 cells contribute to the tissue-resident ILC2 pool after sequential N. brasiliensis exposure. These aims are both innovative in concept (by challenging the current dogma surrounding iILC2 cells) and approach (by using unique reporter mice and genomic systems to track the fate and function of iILC2 cells). This proposal is significant because understanding of the origin of iILC2 cells, how they egress and migrate to inflamed mucosa, and their contribution to the long-term tissue-resident ILC2 population in the lung significantly advances our understanding of ILC2 biology. Filling these key gaps in our knowledge will establish the role of iILC2 cells as both critical first responders to helminth infection and also identify the mechanisms contributing to their role in long-term barrier maintenance and integrity.