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: 10549366
• 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/10549366
• 关键词: Allergic; Allergic Disease; Alveolus; Area; Asthma; Bacterial Infections; Benefits and Risks; Blood; Blood Vessels; CD4 Positive T Lymphocytes; Cells; Data; Diagnostic; Duct (organ) structure; Equilibrium; Fibroblasts; Fibrosis; Future; Genetic; Genetic Transcription; Goals; Helminths; Helper-Inducer T-Lymphocyte; Hematopoietic; Hepatocyte; Home; Hyperactivity; Hypersensitivity; Immune; Immune response; Immunity; Immunophenotyping; Impairment; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Interferon Type II; Interleukin-13; Interleukin-5; Kinetics; Leukocytes; Liver; Location; Lung; Lymphocyte; Lymphocyte Subset; Lymphoid Cell; Mediating; Modeling; Movement; Mus; Organ; Organ Transplantation; Outcome; Papain; Parabiosis; Pathologic; Pathology; Pathway interactions; Physiological; Physiology; Production; Protozoa; Repression; Residencies; Rest; Route; Shapes; Signal Transduction; Site; Source; Stimulus; Stromal Cells; T-Lymphocyte; TSLP gene; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissues; Virus Diseases; Work; atopy; cellular targeting; cytokine; in vivo; mortality; multimodality; repaired; response; tool; trafficking; virtual

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.

项目摘要/摘要： 2型过敏性免疫性是一种免疫响应的专门亚型，它限制了多细胞舵手和 原生动物。但是，最近的工作还实现了生理组织重塑的2型免疫共同体，这在 多余的会驱动过敏，哮喘，特应性和组织纤维化。 2型免疫历史由组织协调驱动 2型先天淋巴样细胞（ILC2）和2型CD4+ T辅助细胞（TH2S）。组织居住的ILC2和TH2 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- 13组织下游免疫和非山地肌细胞。尽管潜水组织信号调节这些 细胞，尚不清楚如何控制器官内部的广泛定位（即地形）以及如何控制 可能会影响免疫病理学。在许多组织中 在较大的血管和肺气道周围。我们的初步数据表明，2型炎症驱动了他们 扩展到新生实质的壁ni（例如，在肺的肺泡附近，肝细胞中的肝细胞）。我们发现ILC2S 需要贩运相关的途径才能扩展到实质壁ni，而1型淋巴细胞（T1L） 广泛分布在组织中，并产生将ILC2和Th2子集限制在冒险壁ni的IFNγ+中。 混合型2型注射型模型，在副部位强制执行的ILC2和TH2S抑制有效的T1L- 介导的反应导致死亡率增加。我们的中心假设是ILC2和TH2定位到 组织副群壁细分市场是通过从血池中贩运进行的，必须严格控制以平衡 免疫风险和器官的益处。 AIM 1将定义IFNγ表达ILC2的机制和影响 和Th2细胞副群分布。我们将检验以下假设，即由T细胞产生的IFNγ限制了细胞 混合炎症期间贩运实质壁ni。我们将使用遗传工具消除IFNγ- 在ILC2和TH2子集上发出信号传导，并确定混合炎症模型中的功能后果。 AIM 2将确定控制ILC2和TH2副群定位的途径和信号。我们会在这里 检验2型免疫史的假设激活2型淋巴细胞扩张和“逆行运输”的组织 在血液中的翻译住宅允许在副部位和最终类型中进行组织特异性重新进入 2个利基扩展。我们将使用多模式方法，包括器官移植，光转换， 抛物线和细胞转移以确定所需的运输分子，动力学，居住时间和最终 副群落场所的命运。 AIM 3将定义ILC2和TH2副群的功能影响和目标 本土化。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基质 子集，潜在地损害有效的1型免疫史，并导致上下文依赖性的有益或病理 结果。成功完成拟议的工作将提供有关组织的基本机械数据 ILC2和TH2S的地形影响功能，为将来的诊断和治疗奠定了基础 可以指导2型定位以影响有益和病理免疫调查的方法。