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.

项目摘要/摘要 感知是任何免疫响应的强制性第一步，导致激活早期的先天信号 直接随后的适应性免疫学。细菌，病毒和真菌的传感已详细定义， 但是，我们对寄生虫（蠕虫）和过敏原的理解是如何启动“ 2型” 免疫力仍然缺乏。第2组先天淋巴样细胞（ILC2）是激活的第一个免疫细胞之一 2型反应，但它们并没有直接感知外国激动剂。相反，主机衍生的信号来自 周围组织激活ILC2。一个这样的信号是白细胞三烯（CYSLT），需要 激活肠道和气道ILC2。随着时间的流逝，ILC2被效应子和记忆Th2细胞所取代 获取类似ILC2的转录和表观遗传表型。这些TH2细胞可以在IL-33中激活 没有抗原，但是CYSLT在推动这种先天函数中的作用尚未进行测试。在肠中， CYSLT必须由上皮簇细胞产生，但簇簇细胞在很大程度上可用于2型气道 在该提案的目标1中，我们试图确定激活气道的CYSLT的细胞来源 蠕虫感染期间的ILC2。在AIM 2中，我们测试了CYSLT信号在Th2效应子和 记忆单元。我们的研究有望揭示组织特异性的范例，用于2型的主动性和维护 免疫，从而提出了治疗干预的新策略。