Natural Th17 cells in allergic airway disease

天然 Th17 细胞在过敏性气道疾病中的作用

• 批准号: 8613435
• 负责人: ANGELA HACZKU
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613435
• 关键词: ARNT gene; Allergens; Antigens; Aspergillus fumigatus; Asthma; Biological Assay; CD4 Positive T Lymphocytes; Cell Survival; Cells; Cellular Stress; Characteristics; Chemotactic Factors; Data; Defect; Development; Disease; Disease model; Dissection; Effector Cell; Ensure; Environment; Family member; Flow Cytometry; Foundations; Future; Generations; Genetic Transcription; Host Defense; Human; Hypoxia; Immune; Immune response; Immune system; Infiltration; Inflammatory; Interleukin-17; Lung; Mediating; Metabolism; Modality; Modeling; Molecular; Mus; Neutrophilia; Pathogenesis; Pathway interactions; Peripheral; Population; Production; Property; Publications; Relative (related person); Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Source; Stress; Supporting Cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Thymus Gland; airway hyperresponsiveness; allergic airway disease; base; cofactor; cytokine; design; human FRAP1 protein; hypoxia inducible factor 1; insight; interleukin-22; mTOR Signaling Pathway; migration; mouse model; neutrophil; novel; pathogen; public health relevance; response; thymocyte; transcription factor

DESCRIPTION (provided by applicant): IL-17 is an essential component of the immune response to many pathogens and allergens. A common source of IL-17 is CD4+ T helper 17 (Th17) cells. These cells differentiate from na¿ve CD4 cells into IL-17 producing cells at peripheral sites and are termed, conventional Th17 cells (cTh17). Recently, we and others discovered another population of IL-17 producing CD4+TCR¿¿+ T cells that differentiate into IL-17 secreting cells during their development in the thymus, prior to their migration into the periphery. These T cells are termed "natural" Th17 (nTh17) cells and are present in humans as well as mice. Recent findings reveal that nTh17 cells migrate to peripheral sites, including the lung, and further suggest these cells may be important in pathological conditions including asthma. Although nTh17 and cTh17 cells have similar cytokine profiles, our preliminary data suggest that nTh17 T cells are not simply CD4 T cells that are primed for IL-17 production in the thymus instead of the periphery, but are fundamentally distinct with specific roles in the immune system. Given the importance of IL-17 early in immune responses, we speculate that during selection, a subset of thymocytes is directed to make IL-17 to ensure the generation of a population capable of rapid IL-17 release. Until recently, it was not possible to distinguish the biologic role of nTh17 and cTh17 cells. However, we have discovered that nTh17 and cTh17 cells utilize different components of the Akt/mTOR/HIF signaling pathway for IL-17 production. Using carefully designed mice with defects in either nTh17 or cTh17 cell development we have the unique opportunity to determine the contribution of nTh17 versus cTh17 cells in airway disease. This proposal is focused on understanding how the molecular signals utilized by nTh17 cells during their development dictate their function following secondary TCR induced activation (Aim 1); and on exploiting the distinct developmental requirements of nTh17 and cTh17 T cells to establish whether they possess distinct roles in a well characterized mouse model of asthma ( Aim 2). In Aim 1 we will determine the role of HIF1¿ in nTh17 cells development and function using mice lacking the ability to signal through this pathway. In Aim 2, we will take advantage of our well-characterized model of Aspergillus fumigatus extract induced asthma to determine the contribution of nTh17 cells to asthma.

描述（由适用提供）：IL-17是许多病原体和过敏原的免疫响应的重要组成部分。 IL-17的常见来源是CD4+ T辅助器17（Th17）细胞。这些细胞从Na�VECD4细胞分化为外围部位的IL-17产生细胞，并称为常规TH17细胞（CTH17）。最近，我们和其他人发现了另一个产生CD4 + TCR» + T细胞的IL-17群体，这些细胞在胸腺发育过程中分化为IL-17分泌细胞，然后再迁移到周围。这些T细胞称为“天然” Th17（NTH17）细胞，并存在于人类和小鼠中。最近的发现表明，NTH17细胞迁移到包括肺在内的周围部位，进一步表明这些细胞在包括哮喘在内的病理条件下可能很重要。尽管NTH17和CTH17细胞具有相似的细胞因子谱，但我们的初步数据表明，NTH17 T细胞不仅是胸腺中IL-17产生的CD4 T细胞，而不是外周，但根本上与免疫系统中的特定作用不同。鉴于IL-17早期在免疫反应中的重要性，我们推测在选择过程中，胸腺细胞的一部分被指示使IL-17确保产生能够快速IL-17释放的人群。直到最近，还无法区分NTH17和CTH17细胞的生物学作用。但是，我们发现NTH17和CTH17细胞利用IL-17产生的Akt/mTOR/HIF信号通路的不同组件。使用精心设计的小鼠在NTH17或CTH17细胞开发中具有缺陷，我们有独特的机会来确定NTH17与CTH17细胞在气道疾病中的贡献。提案的重点是了解NTH17细胞在发育过程中使用的分子信号如何决定其继发性TCR引起的激活后其功能（AIM 1）；并利用NTH17和CTH17 T细胞的不同发育需求来确定它们是否在表征良好的哮喘小鼠模型中具有独特的作用（AIM 2）。在AIM 1中，我们将使用缺乏通过该途径发信号的小鼠来确定HIF1缺在NTH17细胞开发和功能中的作用。在AIM 2中，我们将利用我们特征良好的烟曲霉提取物诱导哮喘的模型，以确定NTH17细胞对哮喘的贡献。