Natural Th17 cells in allergic airway disease

天然 Th17 细胞在过敏性气道疾病中的作用

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：IL-17 是对许多病原体和过敏原的免疫反应的重要组成部分 IL-17 的常见来源是 CD4+ T 辅助细胞 17 (Th17)，这些细胞由 na? 细胞分化而来。最近，我们和其他人发现了另一个产生 CD4+TCR 的 IL-17 细胞群。 ¿ + 在胸腺中发育并迁移到外周之前分化为 IL-17 分泌细胞的 T 细胞被称为“天然”Th17 (nTh17) 细胞，存在于人类和小鼠体内。研究结果表明，nTh17 细胞迁移到包括肺部在内的外周部位，并表明这些细胞可能在包括哮喘在内的病理状况中发挥重要作用，尽管 nTh17 和 cTh17 细胞具有相似的细胞因子特征，但我们的初步数据表明： nTh17 T 细胞不仅仅是在胸腺（而不是外周）中产生 IL-17 的 CD4 T 细胞，而且在免疫系统中具有特定的作用，因此在免疫系统中发挥着重要作用。推测在选择过程中，胸腺细胞的子集被引导产生 IL-17，以确保产生能够快速释放 IL-17 的群体，直到最近，还不可能区分 nTh17 和 TH17 的生物学作用。 cTh17 细胞。然而，我们发现 nTh17 和 cTh17 细胞利用 Akt/mTOR/HIF 信号通路的不同成分来产生 IL-17。使用精心设计的具有 nTh17 或 cTh17 细胞发育缺陷的小鼠，我们有独特的机会确定 nTh17 与 cTh17 细胞在气道疾病中的作用该提案的重点是了解 nTh17 细胞在发育过程中利用的分子信号如何决定其继发 TCR 诱导激活后的功能。（目标 1）；并利用 nTh17 和 cTh17 T 细胞的不同发育要求来确定它们在明确表征的哮喘小鼠模型中是否具有不同的作用（目标 2），我们将确定 HIF1 的作用。在目标 2 中，我们将利用我们已充分表征的烟曲霉提取物诱导哮喘模型来确定 nTh17 细胞对哮喘的影响。