Homing of Functionally Distinct ILC Subsets

功能不同的 ILC 子集的归位

• 批准号: 9228316
• 负责人: CHANG H KIM
• 金额: $ 37.9万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228316
• 关键词: Address; Antigens; B-Lymphocytes; Bacterial Infections; Behavior; Biology; Bone Marrow; CCR6 gene; CCR9 gene; CXCR3 gene; Cell physiology; Chronic; Data; Development; Effector Cell; Epithelial; Homing; Homing Behavior; Host Defense; Immune response; Immunity; Immunology; Infection; Inflammation; Inflammatory Response; Interferons; Intestines; Knowledge; Lung; Lymphocyte; Lymphocyte Subset; Lymphoid Cell; Lymphoid Tissue; Marrow; Mediating; Mucous Membrane; Natural Immunity; Organ; Outcome; Phenotype; Play; Population; Positioning Attribute; Recruitment Activity; Regulation; Research; Role; Secondary to; Site; T-Lymphocyte; Testing; Thromboplastin; Time; Tissues; Work; cell motility; cytokine; fighting; hematopoietic tissue; immune function; insight; interest; migration; novel; novel strategies; pathogen; population migration; progenitor; programs; public health relevance; receptor; receptor expression; tissue repair; tissue tropism; trafficking; ward

 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.

 描述（由申请人提供）：对屏障组织中病原体的最佳免疫反应需要及时调节淋巴细胞向淋巴组织和效应位点的募集。先天淋巴样细胞（ILC）是淋巴谱系的细胞，富含于粘膜组织中。它们在对抗病原体、诱导淋巴组织发育和加强上皮屏障功能方面发挥着重要作用。 ILC 被细分为具有不同效应细胞因子表型的三个主要子集：ILC1 产生 Th1 细胞因子 IFN-γ，ILC2 产生 Th2 细胞因子，ILC3 产生 Th17 细胞因子。该领域的一个主要问题是我们对 ILC 子集的迁移程序缺乏了解。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以实现发育和效应功能。我们的初步数据表明，ILC 可能拥有高度复杂的迁移程序来支持其发育和效应器功能。特别是，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 子集经历潜在不同的归巢受体转换，从生成位点迁移到淋巴组织，然后迁移到效应位点。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。为了检验假设并获得有关 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 子集的共享和差异迁移程序。目标 2. 确定 HR 在 ILC 迁移和组织向性中的作用。目标 3. 确定 HR 对 ILC 子集效应器功能的影响。该项目将产生有关 ILC 在体内迁移和分布的基础知识，特别强调 ILC 子集特定的贩运。将鉴定对 ILC 效应器功能重要的归巢受体以及调节这些受体表达的因素。研究结果将为屏障组织中 ILC 免疫的建立提供新的见解。