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

T 细胞中 Blimp-1 的肺特异性表达和功能影响过敏性哮喘

• 批准号: 10209586
• 负责人: Amanda Catherine Poholek
• 金额: $ 52.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-14 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209586
• 关键词: Allergens; Allergic; Allergic Disease; Asthma; Autoimmunity; Automobile Driving; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chronic; Data; Dendritic Cells; Development; Disease; Effector Cell; Exposure to; Extrinsic asthma; GATA3 gene; Generations; Health; Healthcare; Hour; Human; ITGAX gene; Immune; Immune response; Immunity; Immunization; In Situ; Inflammation; Inflammatory; Inhalation; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Kinetics; Lung; Lung Inflammation; Mediastinal lymph node group; Mediating; Memory; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Production; Pyroglyphidae; Reporter; Reporting; Research; Role; Route; STAT3 gene; Shapes; Site; Skin; Structure of parenchyma of lung; System; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Tamoxifen; Testing; Th2 Cells; Therapeutic; Tissues; Transcription Repressor; United States; Work; adaptive immune response; airway inflammation; cell type; chronic inflammatory lung disease; cytokine; effector T cell; environmental allergen; inflammatory milieu; memory CD4 T lymphocyte; mouse model; novel; recruit; response; therapeutic development; therapeutic target; transcriptome; transcriptome sequencing

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.

项目概要 过敏性哮喘是一种肺部慢性炎症性疾病，可驱动 2 型细胞因子反应（例如 IL- 4、IL-5 和 IL-13）主要由 Th2 表型的活化 CD4 T 细胞响应暴露而产生 与环境过敏原。已知主转录因子 GATA3 可驱动 Th2 发育， 促进 2 型细胞因子的产生，然而，驱动 Th2 细胞对过敏原的分子途径 启动和回忆阶段尚不清楚。我们已经报道过 Blimp-1 是一个意想不到的驱动程序 过敏性哮喘的发生对于促进肺部和随后气道中 Th2 细胞的发育至关重要 炎。 Blimp-1 是一种转录抑制因子，由效应 T 细胞多效性表达，可以 调节效应细胞反应以限制 T 细胞介导的自身免疫。该提案的目的是 了解促进 Blimp-1 表达以驱动 Th2 的肺部组织特异性环境生态位 肺部的发育以及随后响应过敏原的炎症。我们已经证明 IL-10- STAT3-Blimp-1 轴对于 Blimp-1 促进 Th2 细胞响应吸入过敏原至关重要。我们现在 假设吸入过敏原会产生肺部特异性炎症环境以促进 Blimp-1 并驱动 Th2 细胞在对过敏原的初级反应和记忆反应中分化，从而导致慢性循环 肺部炎症。我们将通过三个目标来探索这个假设：(1) 证明 Blimp-1 的表达 需要来自肺源性迁移cDC2的IL-10，该cDC2是响应吸入过敏原而产生的。 (2) 判断是否 T 细胞中 Blimp-1 表达的动力学是其驱动 Th2 分化的环境依赖性功能的基础 或限制效应T细胞。 (3) 证明过敏原特异性记忆 T 细胞需要 Blimp-1 来驱动 Th2 回忆肺部的反应。总的来说，我们将确定 Blimp-1 在 Th2 细胞从头生成中的作用，以 驱动 2 型生态位并促进持续炎症。这项研究意义重大，因为它有可能 确定调节 Th2 细胞响应慢性过敏原的途径，并阐明背景 Blimp-1 的依赖功能，Blimp-1 是效应 T 细胞分化和功能的重要调节因子。这部作品 因此，将展示如何在治疗中考虑组织特异性和环境依赖性免疫 与组织相关的疾病（例如过敏性哮喘）的治疗方法。