The role of PU.1 in T helper cell heterogeneity

描述（由申请人提供）：PU.1是ETS家族转录因子，对包括巨噬细胞、B细胞、肥大细胞和中性粒细胞在内的多种造血谱系的发展至关重要。在之前的研究中，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的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。pu1缺陷的Th2细胞产生Th2细胞因子增加，细胞因子分泌的均一性增加，分泌两种或两种以上细胞因子的细胞增多。因此，PU.1调节Th2群体的异质性。在上一个授权期内，我们还证明了在最近描述的小鼠和人类培养的Th9细胞群中，PU.1是IL-9表达所必需的，并且PU.1在Th9中的表达水平高于Th2细胞。我们进一步表明，在T细胞特异性缺失PU.1的小鼠中，变应性炎症的发展减少，与IL-9和Th2趋化因子的表达减少相关。这表明在过敏性炎症的发展中需要PU.1，这一过程被认为主要依赖于Th2细胞。在本研究中，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生过程中对PU.1依赖性Th9细胞的需求。我们的假设是，PU.1是2型炎症的重要调节因子，并且PU.1依赖于Th2/Th9表型的调节是过敏性炎症发生的关键组成部分。我们这个提案的目标是1。明确在诱导和自发模型系统中介导过敏性炎症对PU.1的要求；2. 确定PU.1调节IL-9能力的结构和功能要求；和3。明确PU.1对il -9分泌T细胞表型可塑性和稳定性的要求。我们这项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在指导这种表型中的作用。从这些研究中获得的信息将使我们更好地了解该亚群在过敏性炎症中的作用，以及如何针对该亚群或其功能开发用于治疗人类过敏性疾病。

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.