A myeloid sentinel that secretes leukotrienes to activate type 2 immunity

分泌白三烯以激活 2 型免疫的骨髓前哨细胞

基本信息

批准号：
10659251
负责人：
Jakob H. von Moltke
金额：
$ 22.06万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10659251
关键词：
Address Agonist Allergens Alveolar Macrophages Antigens Attenuated Automobile Driving Bacteria Biology Bone Marrow CD4 Positive T Lymphocytes Cells Chimera organism Cre driver Cytokine Gene Data Enzymes Epigenetic Process Epithelium Event Foundations Genetic Transcription Helminths ITGAX gene Immune Immune response Immunity In Vitro Inflammation Intestines Knowledge Leukotrienes Lung Lymphocyte Lymphoid Cell Maintenance Memory Mus Myelogenous Natural Immunity Phenotype Physiological Positioning Attribute Production Pyroglyphidae Radiation Tolerance Regulation Reporter Role Sentinel Signal Induction Signal Pathway Signal Transduction Small Intestines Source T-Cell Receptor Testing Th2 Cells Therapeutic Intervention Time Tissues Transcription Factor AP-1 Virus adaptive immunity airway inflammation cell type cysteinyl leukotriene receptor cysteinyl-leukotriene cytokine epigenome experimental study fungus helminth infection novel novel therapeutic intervention nuclear factors of activated T-cells receptor response synergism transcription factor transcriptome

项目摘要

Project Summary/Abstract Sensing is the obligate first step of any immune response, resulting in activation of early innate signals that direct subsequent adaptive immunity. The sensing of bacteria, viruses, and fungi has been defined in detail, but our understanding of how parasitic worms (helminths) and allergens are detected to initiate “type 2” immunity remains lacking. Group 2 innate lymphoid cells (ILC2s) are among the first immune cells activated in a type 2 response, but they do not directly sense foreign agonists. Instead, host-derived signals from the surrounding tissues activate ILC2s. One such signal is cysteinyl leukotrienes (cysLT), which are required to activate both intestinal and airway ILC2s. Over time, ILC2s are replaced by effector and memory Th2 cells that acquire an ILC2-like transcriptional and epigenetic phenotype. These Th2 cells can be activated by IL-33 in the absence of antigen, but a role for cysLT in driving this innate-like function has not been tested. In the intestine, cysLTs must be produced by epithelial tuft cells, but tuft cells are largely dispensable for airway type 2 inflammation. In Aim 1 of this proposal, we seek to identify the cellular source of cysLTs that activate airway ILC2s during helminth infection. In Aim 2, we test the cell intrinsic role of cysLT signaling in Th2 effector and memory cells. Our studies promise to reveal tissue-specific paradigms for initiation and maintenance of type 2 immunity, thereby suggesting new strategies for therapeutic intervention.

项目概要/摘要感知是任何免疫反应的必然第一步，导致早期先天信号的激活细菌、病毒和真菌的直接后续适应性免疫已被详细定义，但我们对如何检测寄生虫和过敏原以引发“2 型”的理解第 2 类先天淋巴细胞 (ILC2) 是最先被激活的免疫细胞之一。 2 型反应，但它们不直接感知外来激动剂，而是来自宿主的信号。周围组织激活 ILC2 的信号之一是半胱氨酰白三烯 (cysLT)，它是激活 ILC2 所必需的。激活肠道和气道 ILC2 随着时间的推移，ILC2 会被效应细胞和记忆 Th2 细胞取代。获得类似 ILC2 的转录和表观遗传表型这些 Th2 细胞可被 IL-33 激活。缺乏抗原，但 cysLT 在驱动这种先天性功能中的作用尚未在肠道中进行测试。 cysLT 必须由上皮簇细胞产生，但簇细胞对于 2 型气道来说基本上是可有可无的在该提案的目标 1 中，我们寻求确定激活气道的 cysLT 的细胞来源。蠕虫感染期间的 ILC2 在目标 2 中，我们测试了 cysLT 信号传导在 Th2 效应子和中的细胞内在作用。我们的研究有望揭示 2 型记忆细胞的启动和维持的组织特异性范例。免疫，从而提出了治疗干预的新策略。