Plasticity of IL-9-secreting T cells

分泌 IL-9 的 T 细胞的可塑性

• 批准号: 8318353
• 负责人: Olufolakemi Olaiya Awe
• 金额: $ 3.22万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318353
• 关键词: Address; Allergic Disease; Allergic inflammation; Binding Sites; Cells; DNA Binding; Data; Development; Disease; Ectopic Expression; Environment; Event; Goals; Human; IRF4 gene; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-4; Interleukin-9; Learning; Lung; Maintenance; Modeling; Mus; Phase; Phenotype; Play; Population; Production; Reporter; Role; STAT6 gene; Source; System; T-Lymphocyte; Testing; Th2 Cells; Time; allergic response; cytokine; flexibility; in vivo; proto-oncogene protein Spi-1; research study; transcription factor

DESCRIPTION (provided by applicant): Plasticity of IL-9-secreting T cells T helper subsets, through the secretion of specific cytokines, regulate an array of inflammatory diseases. The differentiation of Th cells into specific cytokine-secreting subsets is highly dependent on the surrounding cytokine environment and the transcription factors expressed within each subset. The Th9 subset, that secretes IL-9 as the defining cytokine, is the latest Th cell population to be described. Our lab recently showed that the transcription factor PU.1 promoted the development of these cells. Both IL-9 and PU.1 expression in T cells are required for maximal infiltration of the lung in models of allergic inflammation. Although, Th9 cells and Th2 cells share obligate transcription factors such as STAT6 and GATA3 and require IL-4 for their development, there is evidence that Th9 cells are a unique Th cell subset. PU.1 represents a switch factor by repressing Th2 cytokines and inducing IL-9. Thus, Th2 cells can acquire IL-9- secreting potential. However, whether the IL-9-secreting Th9 phenotype is stable, or whether Th9 cells may acquire cytokine expression associated with other Th subsets is not known. In this proposal, we will explore Th9 plasticity, and track Th9 cells to assess phenotype switching in vivo. In our first Aim we will determine the stability and plasticity of Th9 cells that either haveor lack expression of PU.1 using in vitro culture systems. In the second Aim we will generate Il9 reporter and lineage-tracing mice and test the presence and fate of IL-9-expressing cells in models of allergic inflammation. Our overall goal for this application is to define the plasticity f Th9 cells in allergic inflammation, and the role of PU.1 in directing this phenotype. The information learned from these studies will provide a greater understanding of the role this subset plays in allergic inflammation, and how targeting this subset, or its functions, might be developed as therapy for allergic disease in humans. PUBLIC HEALTH RELEVANCE: For many years Th2 cells were the only T cells thought to control allergic inflammation. We present preliminary data that a newly described subset of cells called Th9 cells, are also required for allergic inflammation and in this proposal we investigate the stability, development and function. Results from these studies will provide new information about how allergic disease develops, and how T cells could be targeted for the treatment of allergic disease.

描述（由申请人提供）：分泌IL-9的T细胞的可塑性T辅助细胞亚群通过分泌特异性细胞因子调节一系列炎性疾病。Th细胞分化成特定的分泌精氨酸的亚群高度依赖于周围的细胞因子环境和每个亚群内表达的转录因子。分泌IL-9作为定义细胞因子的Th 9亚群是最新的Th细胞群， 介绍了我们的实验室最近表明，转录因子PU.1促进了这些细胞的发育。T细胞中的IL-9和PU.1表达都是过敏性炎症模型中肺的最大浸润所需的。尽管Th 9细胞和Th 2细胞共享专性转录因子如STAT 6和GATA 3，并且它们的发育需要IL-4，但有证据表明Th 9细胞是独特的Th细胞亚群。PU.1代表通过抑制Th 2细胞因子和诱导IL-9的转换因子。因此，Th 2细胞可以获得IL-9分泌潜能。然而，分泌IL-9的Th 9表型是否稳定，或者Th 9细胞是否可以获得与其他Th亚群相关的细胞因子表达尚不清楚。在这个提议中，我们将探索Th 9可塑性，并跟踪Th 9细胞以评估体内表型转换。在我们的第一个目标中，我们将使用体外培养系统确定具有或缺乏PU.1表达的Th 9细胞的稳定性和可塑性。在第二个目标中，我们将产生IL-9报告基因和谱系追踪小鼠，并测试过敏性炎症模型中IL-9表达细胞的存在和命运。本申请的总体目标是确定Th 9细胞在过敏性炎症中的可塑性，以及PU.1在指导这种表型中的作用。从这些研究中了解到的信息将使人们更好地了解该亚群在过敏性炎症中的作用，以及如何靶向该亚群或其功能，以治疗人类过敏性疾病。 公共卫生相关性：多年来，Th 2细胞被认为是唯一控制过敏性炎症的T细胞。我们目前的初步数据表明，一种新描述的称为Th 9细胞的细胞亚群也是过敏性炎症所需的，在本提案中，我们研究了其稳定性，发育和功能。这些研究的结果将提供有关过敏性疾病如何发展以及T细胞如何靶向治疗过敏性疾病的新信息。