The role of PU.1 in T helper cell heterogeneity

PU.1 在 T 辅助细胞异质性中的作用

• 批准号: 7926645
• 负责人: MARK H KAPLAN
• 金额: $ 38.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926645
• 关键词: Allergic Disease; Allergic inflammation; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; Cells; Data; Development; Ectopic Expression; Family; Gene Deletion; Gene Expression Regulation; Genes; Goals; Grant; Helper-Inducer T-Lymphocyte; Hematopoietic; Heterogeneity; Human; Immunity; Inflammation; Inflammatory; Interleukin-4; Interleukin-9; Learning; Mediating; Mus; Peripheral; Phenotype; Play; Population; Process; Production; RNA Interference; Regulation; Role; Staging; Stem cells; T-Lymphocyte; Th2 Cells; chemokine; cytokine; macrophage; mast cell; neutrophil; public health relevance; transcription factor

DESCRIPTION (provided by applicant): PU.1 is an ETS family transcription factor that is crucial for the development of multiple hematopoietic lineages including macrophages, B cells, mast cells and neutrophils. In the previous grant period we demonstrated that PU.1 is also expressed in T cells, specifically in Th2 cells. PU.1 expression segregates into Th2 populations secreting low levels of IL-4, but promotes the expression of chemokines associated with allergic inflammation. PU.1-deficient Th2 cells have increased Th2 cytokine production and increased homogeneity of cytokine secretion, in that there are more cells secreting two or more cytokines. Thus, PU.1 regulates heterogeneity in Th2 populations. In the last granting period we have also demonstrated that PU.1 is required for IL-9 expression in the recently described Th9 population of Th cells in both mouse and human cultures, and that PU.1 is expressed at higher levels in Th9 than in Th2 cells. We further show that the development of allergic inflammation in mice that have a T cell specific deletion of PU.1 is decreased, correlating with decreased expression of IL-9 and Th2 chemokines. This demonstrates a requirement for PU.1 in the development of allergic inflammation, a process that was thought to depend largely on Th2 cells. In this proposal, we will further explore the role of PU.1 in Th9 cells, both in the context of gene regulation of IL-9, the development of the Th9 phenotype, and the requirement for PU.1-dependent Th9 cells in the development of allergic inflammation. Our hypothesis for this proposal is that PU.1 is an important regulator of type 2 inflammation and that PU.1-depnedent regulation of the Th2/Th9 phenotypes is a critical component of developing allergic inflammation. Our Aims for this proposal are 1. Define the requirement for PU.1 in mediating allergic inflammation in induced and spontaneous model systems; 2. Determine the structural and functional requirements for the ability of PU.1 to regulate IL-9; and 3. Define the requirement for PU.1 in plasticity and stability of the IL-9-secreting T cell phenotype. Our overall goal for this application is to define the role of 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 factors that control their 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）：PU.1是一种ETS家族转录因子，对于包括巨噬细胞、B细胞、肥大细胞和中性粒细胞在内的多种造血谱系的发育至关重要。在之前的资助期间，我们证明了 PU.1 也在 T 细胞中表达，特别是在 Th2 细胞中。 PU.1 表达分离到分泌低水平 IL-4 的 Th2 群体中，但促进与过敏性炎症相关的趋化因子的表达。 PU.1缺陷的Th2细胞增加了Th2细胞因子的产生并增加了细胞因子分泌的同质性，因为有更多的细胞分泌两种或多种细胞因子。因此，PU.1 调节 Th2 群体的异质性。在最后的授权期间，我们还证明了在小鼠和人类培养物中最近描述的 Th9 细胞群中，PU.1 是 IL-9 表达所必需的，并且 PU.1 在 Th9 细胞中的表达水平高于在 Th2 细胞中的表达水平。我们进一步表明，T 细胞特异性删除 PU.1 的小鼠中过敏性炎症的发展减少，这与 IL-9 和 Th2 趋化因子表达的减少相关。这表明过敏性炎症的发展需要 PU.1，这一过程被认为很大程度上依赖于 Th2 细胞。在本提案中，我们将进一步探讨 PU.1 在 Th9 细胞中的作用，包括 IL-9 的基因调控、Th9 表型的发展以及过敏性炎症发展中对 PU.1 依赖性 Th9 细胞的需求。我们对此提议的假设是，PU.1 是 2 型炎症的重要调节因子，并且 PU.1 依赖的 Th2/Th9 表型调节是发生过敏性炎症的关键组成部分。我们此提案的目标是 1. 明确 PU.1 在诱导和自发模型系统中介导过敏性炎症的要求； 2.确定PU.1调节IL-9能力的结构和功能要求； 3. 定义 PU.1 在分泌 IL-9 的 T 细胞表型的可塑性和稳定性方面的要求。我们此应用的总体目标是确定 Th9 细胞在过敏性炎症中的作用，以及 PU.1 在指导该表型中的作用。从这些研究中获得的信息将有助于更好地了解该子集在过敏性炎症中所起的作用，以及如何开发针对该子集或其功能的疗法来治疗人类过敏性疾病。 公共卫生相关性：多年来，Th2 细胞被认为是唯一能够控制过敏性炎症的 T 细胞。我们提供的初步数据表明，新描述的称为 Th9 细胞的细胞子集也是过敏性炎症所必需的，在本提案中，我们研究了控制其发育和功能的因素。这些研究的结果将提供有关过敏性疾病如何发展以及如何靶向 T 细胞治疗过敏性疾病的新信息。