Lung-specific expression and function of Blimp-1 in T cells impacting allergic asthma

项目总结 过敏性哮喘是一种慢性肺部炎症性疾病，可驱动2型细胞因子反应(如IL-1和IL-2)。 4、IL-5和IL-13)主要由Th2表型的活化的CD4T细胞产生 与环境过敏原有关。已知的主要转录因子GATA3驱动Th2的发育和 然而，促进2型细胞因子的产生，是驱动Th2细胞产生过敏原的分子途径 启蒙和回忆阶段还没有被很好地理解。我们已经报道过Blimp-1是一个意想不到的驱动程序 过敏性哮喘对促进肺和随后的呼吸道中Th2细胞的发育至关重要 发炎。BLIMP-1是一种转录抑制因子，由效应器T细胞多向性表达 调节效应细胞反应以抑制T细胞介导的自身免疫。这项建议的目的是 了解促进Blimp-1表达以驱动Th2的肺组织特定环境利基 肺部的发展和随后对过敏原的炎症反应。我们已经证明了IL-10- STAT3-Blimp-1轴对Blimp-1促进Th2细胞对吸入性变应原的反应至关重要。我们现在 假设吸入变应原会产生肺特异性炎症环境来促进Blimp-1 并推动分化的Th2细胞在原代和记忆中对变应原做出反应，导致慢性 肺部发炎。我们将从三个方面探讨这一假说：(1)证明Blimp-1的表达 需要来自肺来源的迁移性CDC2的IL-10，这些CDC2是对吸入变应原的反应。(2)确定是否 Blimp-1在T细胞中的表达动力学是其驱动Th2分化的上下文依赖功能的基础 或限制效应器T细胞。(3)证明变应原特异性记忆T细胞需要Blimp-1来驱动Th2 回忆起肺部的反应。总之，我们将确定Blimp-1在Th2细胞从头生成中的作用 推动2型利基市场，促进持续性炎症。这项研究具有重要意义，因为它有可能 确定调节Th2细胞对慢性变应原的反应的途径，以及阐明其背景- Blimp-1的依赖功能，它是效应T细胞分化和功能的重要调节因子。这部作品 因此将展示如何组织特异性和上下文依赖的免疫必须在 与组织相关疾病的治疗方法，如过敏性哮喘。

PROJECT SUMMARY Allergic asthma is a chronic inflammatory disease of the lung that drives a type 2 cytokine response (such as IL- 4, IL-5, and IL-13) predominately produced by activated CD4 T cells of a Th2 phenotype in response to exposure with environmental allergens. The master transcription factor GATA3 is known to drive Th2 development and promote type 2 cytokine production, however, the molecular pathways that drive Th2 cells to allergens at both the initiation and recall stages are not well understood. We have reported that Blimp-1 is an unexpected driver of allergic asthma that is critical to promote Th2 cell development in the lung and subsequent airway inflammation. Blimp-1 is a transcriptional repressor that is pleiotropically expressed by effector T cells and can regulate effector cell responses to constrain T cell-mediated autoimmunity. The purpose of this proposal is to understand the tissue-specific environmental niche of the lung that promotes Blimp-1 expression to drive Th2 development in the lung and subsequent inflammation in response to allergens. We have shown that the IL-10- STAT3-Blimp-1 axis is critical for Blimp-1 to promote Th2 cells in response to inhaled allergens. We now hypothesize that inhalation of allergens creates a lung-specific inflammatory environment to promote Blimp-1 and drive differentiation Th2 cells in both primary and memory responses to allergen leading to cycle of chronic lung inflammation. We will explore this hypothesis in three aims: (1) Demonstrate that expression of Blimp-1 requires IL-10 from lung-derived migratory cDC2s produced in response to inhaled allergens. (2) Determine if the kinetics of Blimp-1 expression in T cells underlie its context-dependent function to drive Th2 differentiation or constrain effector T cells. (3) Demonstrate that allergen-specific memory T cells require Blimp-1 for Th2 driven recall responses in the lung. Overall, we will determine the role of Blimp-1 in de novo generation of Th2 cells to drive a type 2 niche and promote persistent inflammation. This study is significant because of its potential to identify pathways regulating Th2 cells in response to chronic allergens, as well as to elucidate the context- dependent function of Blimp-1, an important regulator of effector T cell differentiation and function. This work therefore will demonstrate how tissue-specific and context-dependent immunity must be considered in therapeutic approaches for diseases associated with tissues such as allergic asthma.