Differentiation of Th2 cytokine-producing innate cells

产生 Th2 细胞因子的先天细胞的分化

• 批准号: 7082905
• 负责人: HUA HUANG
• 金额: $ 34.28万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082905
• 关键词: asthma; cell differentiation; cytokine; helper T lymphocyte; hematopoietic stem cells; immune response; immunogenetics; interleukin 4; interleukin 5; laboratory mouse; transcription factor

DESCRIPTION (provided by applicant): Airway inflammation induced by various allergens, pollution, and infections is a major underlying cause of asthma, a disease with alarming increases in incidence and mortality in the western countries in the past two decades. We seek to understand the cellular and molecular basis for exacerbation of asthma. Our immediate goal is to investigate the mechanisms by which CD4+ T helper cells (Th) regulate differentiation of innate Th2-type effector cells. Both CD4+ Th 2 cells and Th2-type innate effector cells have been shown to play critical roles in causing allergic airway inflammation by producing interleukin (IL)-4, IL-5, IL-9, IL-13 and IL-25. However, the mechanisms by which CD4+ Th2 cells regulate innate Th2-type effector cells are unknown. We studied these mechanisms by using IL-4 reporter mice. We found that IL-4 plays an important role in the differentiation of Th2 cytokine-producing innate cells both in vivo and in vitro. Based on our preliminary findings, we hypothesize that IL-4 primes bone marrow progenitor cells into Th2-type innate effector cells via a GATAS-dependent mechanism, while IL-5 does so via TAT5/GATA1-dependent mechanisms. We propose three specific aims to test our hypothesis. in Aim 1, we will determine whether CD4+Th2 effector cells coordinate with innate cells to generate Th2-type immunity through secretion of IL-4 and IL-5. In Aim 2, we will determine whether IL-4 directs bone marrow progenitor cells to differentiate into innate Th2-type effector cells via a GATA3-dependent mechanism; and In Aim 3, we will determine whether IL-5 directs bone marrow progenitor cells to differentiate into Th2-type innate effector cells via a STAT5/GATA1-dependent mechanism. These studies will identify novel aspects of interaction between adaptive immunity and innate cells. For diseases such as allergic inflammation, asthma, parasitic infection, and other immune dysregulations, our findings could lead to more effective treatments.

描述(申请人提供)：由各种过敏原、污染和感染引起的呼吸道炎症是哮喘的主要潜在原因，哮喘是一种在过去20年中在西方国家发病率和死亡率惊人地上升的疾病。我们试图了解哮喘恶化的细胞和分子基础。我们的近期目标是研究CD4+T辅助细胞(Th)调节先天Th2型效应细胞分化的机制。研究表明，CD4+Th2细胞和Th2型先天效应细胞均通过产生IL-4、IL-5、IL-9、IL-13和IL-25在引起过敏性呼吸道炎症中发挥关键作用。然而，CD4+Th2细胞调节先天Th2型效应细胞的机制尚不清楚。我们用IL-4报告鼠研究了这些机制。我们发现在体内和体外，IL-4在Th2细胞因子产生的天然细胞分化过程中起着重要的作用。根据我们的初步发现，我们假设IL-4通过GATAS依赖的机制启动骨髓祖细胞转化为Th2型先天效应细胞，而IL-5通过TAT5/GATA1依赖的机制启动Th2型先天效应细胞。我们提出了三个具体目标来检验我们的假设。在目标1中，我们将确定CD4+Th2效应细胞是否与天然细胞协同，通过分泌IL-4和IL-5来产生Th2型免疫。在目标2中，我们将确定IL-4是否通过GATA3依赖的机制引导骨髓祖细胞分化为先天Th2型效应细胞；在目标3中，我们将确定IL-5是否通过STAT5/GATA1依赖的机制引导骨髓前体细胞分化为Th2型先天效应细胞。这些研究将确定获得性免疫和先天细胞之间相互作用的新方面。对于过敏性炎症、哮喘、寄生虫感染和其他免疫失调等疾病，我们的发现可能会导致更有效的治疗。