The role of PU.1 in T helper cell heterogeneity

描述（由申请人提供）：PU.1是一种ETS家族转录因子，其对于多种造血谱系（包括巨噬细胞、B细胞、肥大细胞和中性粒细胞）的发育至关重要。在之前的授权期间，我们证明了PU.1也在T细胞中表达，特别是在Th 2细胞中。PU.1表达分离成分泌低水平IL-4的Th 2群体，但促进与过敏性炎症相关的趋化因子的表达。PU.1缺陷型Th 2细胞具有增加的Th 2细胞因子产生和增加的细胞因子分泌的均一性，因为有更多的细胞分泌两种或更多种细胞因子。因此，PU.1调节Th 2群体的异质性。在最后一个授权期，我们还证明了PU.1是最近描述的小鼠和人培养物中Th细胞的Th 9群体中IL-9表达所必需的，并且PU.1在Th 9中的表达水平高于在Th 2细胞中的表达水平。我们进一步表明，具有T细胞特异性PU.1缺失的小鼠中过敏性炎症的发展减少，与IL-9和Th 2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，这一过程被认为在很大程度上依赖于Th 2细胞。在这项提案中，我们将进一步探索PU.1在Th 9细胞中的作用，包括IL-9的基因调控，Th 9表型的发展以及过敏性炎症发展中对PU.1依赖性Th 9细胞的需求。我们对这一提议的假设是PU.1是2型炎症的重要调节剂，并且PU.1依赖性调节Th 2/Th 9表型是发展过敏性炎症的关键组成部分。我们提出这个建议的目的是1。确定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的能力的结构和功能要求;和3.定义PU.1在IL-9分泌性T细胞表型的可塑性和稳定性方面的要求。本申请的总体目标是确定Th 9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。我们提出的初步数据表明，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T细胞如何靶向治疗过敏性疾病的新信息。

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.