The role of PU.1 in T helper cell heterogeneity

描述(申请人提供)：PU.1是一种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系的发育至关重要。在之前的授权期中，我们证明了PU1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，但促进与过敏性炎症相关的趋化因子的表达。PU1缺陷的Th2细胞增加了Th2细胞因子的产生，增加了细胞因子分泌的均质性，因为有更多的细胞分泌两种或两种以上的细胞因子。因此，PU1调节Th2群体的异质性。在上一次授予期间，我们还证明了PU.1是最近在小鼠和人类培养的Th9细胞群中表达IL-9所必需的，并且PU.1在Th9细胞中的表达水平高于Th2细胞。我们进一步证明，具有T细胞特异性PU.1缺失的小鼠的过敏性炎症的发生减少，这与IL-9和Th2趋化因子的表达减少有关。这表明在过敏性炎症的发展过程中需要PU1，这一过程被认为在很大程度上依赖于Th2细胞。在这个方案中，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PU.1依赖的Th9细胞在变态反应性炎症发展中的需求。我们对这一提议的假设是，PU.1是2型炎症的重要调节因子，PU1依赖的Th2/Th9表型调节是发生变态反应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PU1在诱导和自发模型系统中介导变态反应性炎症的需求；2.确定PU1调节IL-9能力的结构和功能要求；3.确定PU1在分泌IL-9的T细胞表型的可塑性和稳定性中的需求。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。 与公共卫生相关：多年来，Th2细胞被认为是唯一被认为可以控制过敏性炎症的T细胞。我们提供了初步数据，即新描述的一种称为Th9细胞的细胞亚群也是变态反应性炎症所必需的，在这项建议中，我们研究了控制其发展和功能的因素。这些研究的结果将提供关于过敏性疾病如何发展的新信息，以及T细胞如何被靶向治疗过敏性疾病。

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.