Homing of Functionally Distinct ILC Subsets

 描述（由申请方提供）：对屏障组织中病原体的最佳免疫应答需要及时调节淋巴细胞募集至淋巴组织和效应部位。先天性淋巴样细胞（ILC）是淋巴样谱系的细胞，并且在粘膜组织中富集。它们在抵抗病原体、诱导淋巴组织发育和加强上皮屏障功能方面发挥重要作用。ILC被细分为具有不同效应细胞因子表型的三个主要亚群：ILC 1产生Th 1细胞因子IFN-γ，ILC 2产生Th 2细胞因子，ILC 3产生Th 17细胞因子。该领域的一个主要问题是我们缺乏对ILC子集的迁移程序的理解。虽然ILC在屏障组织中富集并以组织特异性方式分布，但我们目前不了解ILC如何迁移到这些组织中进行发育和效应功能。我们的初步数据提出了ILC具有高度复杂的迁移程序以支持其发育和效应器功能的可能性。特别地，数据表明某些归巢受体调节ILC亚群的组织特异性群体、迁移和功能。我们假设ILC亚群经历了潜在的不同归巢受体开关，从生殖部位迁移到淋巴组织，然后到效应部位。此外，这些归巢受体开关可能在骨髓和外周中的ILC发育的多个阶段受到细胞因子和组织因子的调节。为了检验这一假设，并获得有关ILC迁移的详细信息，我们设计了以下三个具体目标：目标1。确定ILC子集的共享和差分迁移方案。目标二。确定HR在ILC迁移和组织向性中的作用。目标3.确定HR对ILC亚群效应子功能的影响。该项目将产生关于国际劳工组织在人体内的迁移和分布的基本知识，特别强调国际劳工组织特定亚群的贩运。归巢受体对ILC效应器功能和调节这些受体表达的因子很重要，将被鉴定。这些结果将为屏障组织中ILC免疫的建立提供新的见解。

 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.