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型变态反应性免疫是一种特殊的免疫反应亚型，可限制多细胞蠕虫和 原生动物。然而，最近的研究也表明，2型免疫与生理性组织重塑有关，后者在 过量会导致过敏、哮喘、过敏症和组织纤维化。2型免疫是由组织协调驱动的 2型固有淋巴样细胞(ILC2s)和2型CD4+T辅助细胞(Th2s)。组织驻留的ILC2s和Th2s 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-5 13组织下游免疫和非造血细胞。尽管不同的组织信号调节这些 细胞，目前还不清楚它们在器官中的广泛定位(即地形)是如何控制的，以及如何控制的。 可能会影响免疫病理。在许多组织中，ILC2和Th2s定位于富含成纤维细胞的外膜区域 在较大的血管和肺气道周围。我们的初步数据显示，2型炎症导致了他们的 向新生的实质壁龛扩张(例如，肺泡附近，肝脏中的肝细胞)。我们发现ILC2 需要与贩运相关的途径才能扩展到实质壁龛，而1型淋巴细胞(T1L) 在组织中广泛分布，产生干扰素γ+，将ILC2和Th2亚群限制在外膜壁龛内。在……里面 1/2型混合型炎症模型，实质部位ILC2和Th2s增强抑制有效的T1L- 介导性反应导致死亡率增加。我们的中心假设是ILC2和Th2定位于 组织实质壁龛通过从血池中转移而发生，必须严格控制以平衡 对器官的免疫风险和益处。目标1将确定干扰素γ抑制ILC2的机制(S)及其影响 Th2细胞实质分布。我们将验证T细胞产生的干扰素γ限制细胞的假设 在混合性炎症期间向实质壁龛转移。我们将使用基因工具消除干扰素γ- ILC2和Th2亚群上的信号并确定混合性炎症模型中的功能后果。 目标2将确定控制ILC2和Th2实质定位的途径和信号。在这里，我们将 检验第二型免疫激活组织第二型淋巴细胞扩张和“逆行运输”的假设， 在血液中短暂滞留，允许组织特异性重新进入实质部位和终末型 2生态位扩张。我们将使用多种方式，包括器官移植、光转换、 异种共生和细胞转移，以确定所需的运输分子、动力学、停留时间和最终 命运在实质性的地方。目标3将确定ILC2和Th2实质的功能影响和目标 本地化。在这里，我们将测试IL-13和其他信号的产生如何针对离散组织、免疫和间质 亚集，潜在地损害有效的1型免疫，并导致上下文依赖的有益或病理 结果。拟议工作的成功完成将提供有关组织如何 ILC2s和Th2s影响功能的地形图，为未来的诊断和治疗奠定基础 可指导2型本地化以影响有益和病理性免疫反应的方法。