Homing of Functionally Distinct ILC Subsets

 描述(由申请人提供)：在屏障组织中对病原体的最佳免疫反应需要及时调节淋巴组织和效应部位的淋巴细胞募集。先天淋巴样细胞(ILCs)是淋巴系的细胞，在粘膜组织中丰富。它们在对抗病原体、诱导淋巴组织发育和增强上皮屏障功能方面发挥着重要作用。ILC分为三个主要亚群，具有不同的效应细胞因子表型：ILC2产生Th1型细胞因子干扰素-，ILC2产生Th2型细胞因子，ILC3产生Th17型细胞因子。该领域的一个主要问题是我们对ILC子集的迁移计划缺乏了解。虽然ILCs在屏障组织中丰富，并以组织特异性的方式分布，但我们目前尚不清楚ILCs如何迁移到这些组织中以实现发育和效应功能。我们的初步数据表明，ILC有高度复杂的迁移计划，支持其发育和效应器功能。特别是，这些数据表明，某些归巢受体调节组织特异性的群体、迁移和ILC亚群的功能。我们假设ILC亚群经历了潜在的不同的归巢受体开关，从生殖部位迁移到淋巴组织，然后迁移到效应部位。此外，这些归巢受体开关可能在骨髓和外周ILC发育的多个阶段受到细胞因子和组织因子的调节。为了验证假设并获得关于ILC迁移的详细信息，我们设计了以下三个具体目标：目的1.确定ILC子集的共享和差异迁移方案。目的2.确定HRs在ILC迁移和组织趋向性中的作用。目的3.确定HRs对ILC亚群效应功能的影响。该项目将产生关于国际法委员会在机构内的迁移和分布的基本知识，特别强调针对国际法委员会特定子集的贩运。对ILC效应器功能至关重要的归巢受体以及调节这些受体表达的因素将被确定。这一结果将为在屏障组织中建立ILC免疫提供新的见解。

 DESCRIPTION (provided by applicant): Optimal immune responses to pathogens in barrier tissues require timely regulation of lymphocyte recruitment to lymphoid tissues and effector sites. Innate lymphoid cells (ILCs) are cells of the lymphoid lineage and are enriched in mucosal tissues. They play important roles in fighting pathogens, inducing lymphoid tissue development and strengthening epithelial barrier function. ILCs are sub-divided into three major subsets with distinct effector cytokine phenotype: ILC1 produce the Th1 cytokine IFN-, ILC2 produce Th2 cytokines, and ILC3 produce Th17 cytokines. A major problem in the field is our lack of understanding of the migration program of ILC subsets. While ILCs are enriched in barrier tissues and distributed in a tissue-specific manner, we currently don't understand how ILCs migrate to these tissues for development and effector function. Our preliminary data raised the possibility that ILCs have highly sophisticated migration programs that support their development and effector function. Particularly, the data suggest that certain homing receptors regulate tissue-specific population, migration, and function of ILC subsets. We hypothesize that ILC subsets undergo potentially distinct homing receptor switches to migrate from the generative sites to lymphoid tissues and then to effector sites. Moreover, these homing receptor switches are likely to be regulated at multiple stages of ILC development in the bone marrow and periphery by cytokines and tissue factors. To test the hypothesis and obtain detailed information regarding ILC migration, we devised the following three specific aims: Aim 1. Determine the shared and differential migration programs of ILC subsets. Aim 2. Determine the roles of HRs in ILC migration and tissue tropism. Aim 3. Determine the impact of HRs on effector functions of ILC subsets. The project will generate fundamental knowledge on ILC migration and distribution in the body with a special emphasis on ILC subset-specific trafficking. Homing receptors important for ILC effector function and the factors that regulate the expression of these receptors will be identified. The outcomes will provide novel insights into the establishment of ILC immunity in barrier tissues.