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

项目摘要 世界卫生组织估计，全世界每4人中就有1人感染土壤传播的蠕虫。 保护或清除这些寄生虫需要启动2型免疫反应。多产 2型免疫和清除蠕虫依赖于三种关键的细胞因子：白介素4、白介素5和白介素13。 第二组先天淋巴样细胞(ILC2)是2型细胞因子的重要来源。具体而言，ILC2细胞 感知受损的粘膜，并作为抗蠕虫免疫的早期协调者。目前，我们的大部分 对ILC2细胞在抗蠕虫免疫中作用的理解源于专注于组织- 常驻ILC2或自然ILC2(NILC2)小区。然而，我们和其他人最近描述了第二个子集 迁移的ILC2s，称为炎性ILC2细胞(IILC2)。不同的表型、时间、起源和功能 这些不同的ILC2亚群表明，iILC2细胞在抗蠕虫免疫中发挥着独特的作用。 本文概述的研究将解决我们知识中的以下关键差距：1)S的起源 IILC2细胞，这一点仍然存在争议。2)iILC2细胞如何转运到肺以及它们进入肺的程度 感染期间的实质组织尚不清楚。3)iILC2细胞对组织驻留ILC2群体的影响 目前尚不清楚，它们在长期预防蠕虫方面的作用也没有得到探索。下面的目标 将通过测试中心假设来解决这些知识差距，即起源于 小肠或骨髓前体细胞在进入肺后获得nILC2表型，并对 对反复蠕虫感染后的屏障免疫有显著影响。目标1：确定iILC2的来源和组织 蠕虫感染过程中的异质性。目的2：阐明iILC2迁移和插管的机制。 肺部。目的3：确定iILC2细胞对组织驻留ILC2池的贡献程度 暴露于巴西新月形吸虫。这些目标在概念上都是创新的(通过挑战当前的教条 IILC2细胞周围)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和 IILC2细胞的功能)。这一建议具有重要意义，因为对iILC2细胞的起源、如何 它们离开并迁移到发炎的粘膜，以及它们对长期驻留在组织中的ILC2的贡献 肺中的种群极大地促进了我们对ILC2生物学的理解。填补我们的这些关键空白 知识将确定iILC2细胞既是蠕虫感染的关键第一反应者，也是 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.