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: 10597062
• 负责人: Amanda Catherine Poholek
• 金额: $ 52.82万
• 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/10597062
• 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; Health Care Costs; Hour; Human; ITGAX gene; Immune; Immune response; Immunity; Immunization; In Situ; Inflammation; Inflammatory; Inhalation; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Kinetics; Lung; Mediastinal lymph node group; Mediating; Memory; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Production; Pulmonary Inflammation; 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.

项目摘要 过敏性哮喘是肺部的慢性炎症性疾病，其驱动2型细胞因子应答（如IL-10）。 IL-4、IL-5和IL-13）主要由Th 2表型的活化的CD 4 T细胞响应于暴露而产生 环境过敏原。已知主转录因子GATA 3驱动Th 2发育， 促进2型细胞因子的产生，然而，驱动Th 2细胞对过敏原的分子途径， 启动和回忆阶段还没有得到很好的理解。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，这是至关重要的，以促进Th 2细胞在肺和随后的气道发展 炎症Blimp-1是一种转录抑制因子，由效应T细胞多效性表达， 调节效应细胞应答以限制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Th 2的肺的组织特异性环境生态位 肺中的发展和随后的炎症反应过敏原。我们已经证明IL-10- STAT 3-Blimp-1轴对于Blimp-1促进Th 2细胞响应吸入过敏原至关重要。我们现在 假设吸入过敏原产生肺特异性炎症环境以促进Blimp-1 并在对过敏原的初级和记忆反应中驱动Th 2细胞分化，导致慢性 肺部炎症我们将从三个方面来探讨这一假说：（1）证明Blimp-1的表达与细胞凋亡有关， 需要来自肺源性迁移性cDC 2的IL-10，cDC 2是响应吸入的过敏原而产生的。(2)确定是否 Blimp-1在T细胞中表达的动力学是其驱动Th 2分化的环境依赖性功能的基础 或约束效应T细胞。(3)证明过敏原特异性记忆T细胞需要Blimp-1来驱动Th 2 肺部的回忆反应。总之，我们将确定Blimp-1在Th 2细胞从头产生中的作用， 驱动2型壁龛并促进持续性炎症。这项研究意义重大，因为它有可能 确定调节Th 2细胞对慢性过敏原的反应的途径，以及阐明背景- Blimp-1是效应T细胞分化和功能的重要调节因子。这项工作 因此，将证明如何组织特异性和上下文依赖性免疫必须考虑在 与组织相关的疾病如过敏性哮喘的治疗方法。