Localization and function of tissue type 2 lymphocytes during mixed inflammation

混合炎症过程中组织 2 型淋巴细胞的定位和功能

• 批准号: 10444782
• 负责人: Ari B Molofsky
• 金额: $ 55.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444782
• 关键词: Allergic; Alveolus; Area; Asthma; Benefits and Risks; Blood; Blood Vessels; CD4 Positive T Lymphocytes; Cells; Data; Diagnostic; Equilibrium; Fibroblasts; Fibrosis; Future; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Transcription; Helminths; Hepatocyte; Home; Hypersensitivity; Immune; Immune response; Immunity; Immunophenotyping; Impairment; Inflammation; Interferon Type II; Interleukin-13; Interleukin-5; Kinetics; Leukocytes; Liver; Location; Lung; Lymphocyte; Lymphoid Cell; Mediating; Modeling; Movement; Organ; Organ Transplantation; Outcome; Parabiosis; Pathologic; Pathology; Pathway interactions; Physiological; Physiology; Production; Protozoa; Repression; Residencies; Rest; Route; Signal Transduction; Site; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Time; Tissues; Work; atopy; cell type; cytokine; mortality; multimodality; repaired; response; silver fluoride; tool; trafficking

Project Summary/Abstract: Type 2 allergic immunity is a specialized subtype of immune response that limits multicellular helminths and protozoa. However, recent work also implicates type 2 immunity in physiologic tissue remodeling, which in excess can drive allergy, asthma, atopy, and tissue fibrosis. Type 2 immunity is coordinately driven by tissue type 2 innate lymphoid cells (ILC2s) and type 2 CD4+ T helper cells (Th2s). Tissue-resident ILC2s and Th2s have a high degree of transcriptional and functional similarity, secreting high levels of the cytokines IL-5 and IL- 13 to organize downstream immune and non-hematopoietic cells. Although diverse tissue signals regulate these cells, it remains unclear how their broad localization (i.e. topography) within organs is controlled and how this may impact immune pathology. In many tissues, ILC2s and Th2s localize to fibroblast-rich adventitial areas around larger blood vessels and lung airways. Our preliminary data show that type 2 inflammation drives their expansion into de novo parenchymal niches (e.g. near alveoli in lung, hepatocytes in liver). We find that ILC2s require trafficking-associated pathways to expand into parenchymal niches, whereas type 1 lymphocytes (T1Ls) are broadly distributed in tissues and produce IFNγ+ that confine ILC2s and Th2 subsets to adventitial niches. In models of mixed type 1/type 2 inflammation, enforced ILC2s and Th2s in parenchymal sites inhibit effective T1L- mediated responses leading to increased mortality. Our central hypothesis is that ILC2 and Th2 localization to tissue parenchymal niches occurs via trafficking from blood pools and must be tightly controlled to balance immune risks and benefits to organs. Aim 1 will define the mechanism(s) and impact of IFNγ repression of ILC2 and Th2 cell parenchymal distribution. We will test the hypothesis that IFNγ produced by T-cells restricts cell trafficking into parenchymal niches during mixed inflammation. We will use genetic tools to eliminate IFNγ- signaling on ILC2s and Th2 subsets and determine functional consequences in models of mixed inflammation. Aim 2 will determine the routes and signals that control ILC2 and Th2 parenchymal localization. Here we will test the hypothesis that type 2 immunity activates tissue type 2 lymphocyte expansion and ‘retrograde trafficking’, with transitory residency in the blood allowing for tissue-specific re-entry in parenchymal sites and ultimate type 2 niche expansion. We will use multimodal approaches, including organ transplantation, photoconversion, parabiosis, and cell transfers to determine the required trafficking molecules, kinetics, dwell time, and ultimate fate in parenchymal sites. Aim 3 will define functional impacts and targets of ILC2 and Th2 parenchymal localization. Here we will test how production of IL-13 and other signals target discrete tissue immune and stromal subsets, potentially impairing effective type 1 immunity and leading to context-dependent beneficial or pathologic outcomes. Successful completion of the proposed work will provide fundamental mechanistic data on how tissue topography of ILC2s and Th2s impacts function, laying the groundwork for future diagnostic and therapeutic approaches that can direct type 2 localization to impact beneficial and pathologic immune responses.

项目概要/摘要： 2型过敏性免疫是一种特殊的免疫反应亚型，限制多细胞蠕虫， 原生动物然而，最近的研究也暗示了2型免疫在生理组织重塑中的作用， 过量可导致过敏、哮喘、特应性和组织纤维化。2型免疫由组织协调驱动 2型先天淋巴样细胞（ILC 2）和2型CD 4 + T辅助细胞（Th 2）。组织驻留ILC 2和Th 2 具有高度的转录和功能相似性，分泌高水平的细胞因子IL-5和IL-6， 13组织下游免疫和非造血细胞。虽然不同的组织信号调节这些 细胞，目前尚不清楚它们在器官内的广泛定位（即地形）是如何控制的，以及这是如何实现的。 可能会影响免疫病理学。在许多组织中，ILC 2和Th 2定位于富含成纤维细胞的外膜区域 在更大的血管和肺气道周围。我们的初步数据显示，2型炎症驱动他们的 扩展到新生实质小生境（例如，肺中的肺泡附近，肝中的肝细胞）。我们发现ILC 2 需要运输相关途径扩展到实质小生境，而1型淋巴细胞（T1 Ls） 广泛分布于组织中并产生IFNγ+，其将ILC 2和Th 2亚群限制于外膜小生境。在 混合1型/2型炎症模型、实质部位强化的ILC 2和Th 2抑制有效的T1 L- 介导的反应导致死亡率增加。我们的中心假设是ILC 2和Th 2定位于 组织实质小生境通过从血池运输而发生， 对器官的免疫风险和益处。目的1将明确IFNγ抑制ILC 2的机制和影响 和Th 2细胞的实质分布。我们将检验T细胞产生的IFNγ限制细胞增殖的假设。 在混合性炎症期间运输到实质龛中。我们将使用基因工具来消除IFNγ- ILC 2和Th 2亚群的信号传导，并确定混合性炎症模型中的功能后果。 目的2将确定控制ILC 2和Th 2实质定位的途径和信号。这里我们将 检验2型免疫激活组织2型淋巴细胞扩增和“逆向运输”的假设， 在血液中短暂停留，允许组织特异性再进入实质部位， 2利基扩张。我们将使用多模式方法，包括器官移植，光转化， 共生，和细胞转移，以确定所需的运输分子，动力学，停留时间，和最终 实质部位的结局。目的3将定义ILC 2和Th 2实质细胞的功能影响和靶点 本地化在这里，我们将测试IL-13和其他信号的产生如何靶向离散组织免疫和间质 亚群，可能损害有效的1型免疫力，并导致环境依赖性的有益或病理性 结果。成功完成拟议的工作将提供基本的机械数据， ILC 2s和Th 2s的拓扑结构影响功能，为未来的诊断和治疗奠定基础 这些方法可以指导2型定位以影响有益的和病理性的免疫应答。