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

• 批准号: 10507701
• 负责人: Jakob H. von Moltke
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10507701
• 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; Epithelial; Event; Foundations; Genetic Transcription; Helminths; 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 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; receptor; response; transcription factor; transcriptome

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.

项目总结/摘要 感觉是任何免疫反应的第一步，导致早期先天信号的激活， 直接后续适应性免疫。已经详细定义了细菌、病毒和真菌的传感， 但是我们对寄生虫（蠕虫）和过敏原如何被检测到引发“2型”的理解， 免疫力仍然缺乏。第2组先天性淋巴样细胞（ILC 2）是第一批激活的免疫细胞， 2型反应，但它们不直接感应外源激动剂。相反，来自宿主的信号 周围组织激活ILC 2。一种这样的信号是半胱氨酰白三烯（cysLT），其需要与细胞内的蛋白质结合。 激活肠道和气道ILC 2。随着时间的推移，ILC 2被效应和记忆Th 2细胞取代， 获得ILC 2样转录和表观遗传表型。这些Th 2细胞可以被IL-33激活， 不存在抗原，但cysLT在驱动这种先天样功能中的作用尚未得到测试。在肠道中， cysLT必须由上皮丛细胞产生，但丛细胞主要是气道2型细胞 炎症在该提案的目的1中，我们试图鉴定激活气道的cysLT的细胞来源。 寄生虫感染期间的ILC 2。在目的2中，我们测试了cysLT信号传导在Th 2效应细胞中的细胞内在作用， 记忆细胞我们的研究有望揭示启动和维持2型糖尿病的组织特异性模式。 免疫，从而提出了新的治疗干预策略。