Plasticity of IL-9-secreting T cells

分泌 IL-9 的 T 细胞的可塑性

• 批准号: 8450414
• 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/8450414
• 关键词: Address; Allergic Disease; Allergic inflammation; Binding Sites; Cells; DNA Binding; Data; Development; Disease; Ectopic Expression; Environment; Event; Goals; Health; 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.

描述(由申请人提供)：分泌IL-9的T细胞T辅助细胞亚群的可塑性，通过分泌特定的细胞因子来调节一系列炎症性疾病。Th细胞分化为特定的细胞因子分泌亚群高度依赖于周围的细胞因子环境和每个亚群中表达的转录因子。Th9亚群，分泌IL-9作为定义细胞因子，是最新描述的Th细胞群。我们的实验室最近发现，转录因子PU1促进了这些细胞的发育。在过敏性炎症模型中，T细胞中IL-9和PU.1的表达是最大限度地渗透到肺组织所必需的。尽管Th9细胞和Th2细胞共享STAT6和GATA3等转录因子，并需要IL-4才能发育，但有证据表明Th9细胞是一个独特的Th细胞亚群。PU.1代表一种通过抑制Th2细胞因子和诱导IL-9的开关因子。因此，Th2细胞可以获得分泌IL-9的能力。然而，分泌IL-9的Th9表型是否稳定，或者Th9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。在这个方案中，我们将探索Th9的可塑性，并追踪Th9细胞以评估体内的表型转换。在我们的第一个目标中，我们将使用体外培养系统来确定表达PU1或缺失PU1的Th9细胞的稳定性和可塑性。在第二个目标中，我们将产生IL9报告和谱系追踪小鼠，并在过敏性炎症模型中测试IL-9表达细胞的存在和命运。我们这项应用的总体目标是确定Th9细胞在变态反应性炎症中的可塑性，以及PU.1在指导这一表型中的作用。从这些研究中获得的信息将使我们更好地了解这一亚群在过敏性炎症中所起的作用，以及如何将这一亚群或其功能作为治疗人类过敏性疾病的靶点。