Tissue-specific mediators of allergen-driven type 2 inflammation

过敏原驱动的 2 型炎症的组织特异性介质

• 批准号: 10413240
• 负责人: Amanda Catherine Poholek
• 金额: $ 19.29万
• 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: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413240
• 关键词: Address; Allergens; Allergic; Allergic Disease; Allergic inflammation; Anti-Inflammatory Agents; Antigens; Asthma; Automobile Driving; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; Complex; Data; Dendritic Cells; Development; Disease; Dose; Environment; Exposure to; Extrinsic asthma; Food; Future; GATA3 gene; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; Genomics; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Hour; Human; ITGAX gene; Immune; Immune response; Immunity; Immunization; Individual; Inflammation; Inflammatory; Inhalation; Interleukin-10; Location; Lung; Mediating; Mediator of activation protein; Modeling; Mus; Myeloid Cells; Pathogenesis; Pathway interactions; Patients; Play; Production; Pulmonary Inflammation; Pyroglyphidae; Research; Role; Route; Shapes; Signal Transduction; Skin; Structure of parenchyma of lung; T cell differentiation; T cell response; T-Cell Activation; T-Cell Activation Pathway; T-Cell Development; T-Lymphocyte; Testing; Th2 Cells; Time; Tissues; Transcript; Transcription Repressor; United States; airway inflammation; antigen challenge; base; cell type; cytokine; draining lymph node; epigenome; functional outcomes; imprint; inflammatory lung disease; innovation; innovative technologies; lymph nodes; macrophage; microbial; mucosal site; novel; response; subcutaneous; therapeutic development; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Allergens are a class of innocuous environmental antigens that drive an inappropriate inflammatory immune response in susceptible individuals that is often characterized by type 2 cytokine production from helper T cells (Th2). Inhalation of allergens such as house dust mite leads to allergic inflammation of the lung, yet precisely how allergens drive a type 2 immune response in the lung tissue is not clear. We have previously demonstrated that Blimp-1 plays a central role in Th2 cell differentiation in the lung in response to inhaled allergens. However, administration of the same allergens subcutaneously does not require Blimp-1 for the formation of Th2 cells, suggesting the route of entry and the resident tissue specific immune cells determine the necessity for Blimp-1 in Th2 cell differentiation. We have found in response to inhaled antigens that IL-10 is a key cytokine that promotes Blimp-1 in Th2 cells. Blimp-1 acts by repressing Bcl6, itself a potent suppressor of the canonical transcription factor associated with Th2 cells, GATA3. Based on these data, we propose that unique signals driven by lung cells draining to the lymph node from the local tissue environment during T cell priming impact lung specific responses to allergens by promoting Blimp-1 and thus type 2 immunity. In this proposal we will 1) Determine how allergens support Blimp-1 and Th2 cells via IL-10 using an innovative technology that combines unbiased gene expression analysis with spatial location in the tissue to identify IL-10 producing cells in the lung and lymph nodes and their relationship to T cells expressing Blimp-1. In addition, we will 2) perform scRNAseq and scATACseq to identify how lung-specific environments established prior to allergic sensitization impact the immune response upon allergen challenge. We expect these studies to identify fundamental early steps in T cell priming in the lung draining lymph node in response to lung-derived allergens, demonstrating that tissue-specific environmental signals at homeostasis can shape subsequent immune responses to antigen challenge driving unique T cell differentiation pathways. In addition, our unbiased approaches have the potential to elucidate both the spatial location of early T cell priming pathways but also identify novel mediators that promote type 2 immunity to allergens. These studies therefore will have a fundamental impact on future studies that could identify potential therapeutic targets for the treatment of allergic asthma.

项目摘要 过敏原是一类无害的环境抗原，可驱动不适当的炎症免疫 易感个体的一种反应，其特征通常是辅助性T细胞产生2型细胞因子 （Th2）。吸入过敏原，如屋尘螨，导致肺部过敏性炎症，但恰恰是 过敏原如何驱动肺组织中的2型免疫应答尚不清楚。我们先前已经 证实Blimp-1在响应吸入的IL-10的肺中的Th 2细胞分化中起中心作用。 过敏原然而，皮下施用相同的过敏原不需要Blimp-1用于治疗。 Th 2细胞的形成，表明进入途径和驻留的组织特异性免疫细胞决定 Blimp-1在Th 2细胞分化中的必要性。我们已经发现，在对吸入抗原的应答中，IL-10 促进Th 2细胞中Blimp-1的关键细胞因子。Blimp-1通过抑制Bcl 6发挥作用，Bcl 6本身是一种有效的抑制因子， 与Th 2细胞相关的典型转录因子GATA 3。基于这些数据，我们提出， 在T细胞免疫过程中，肺细胞从局部组织环境引流到淋巴结的独特信号 引发通过促进Blimp-1并因此促进2型免疫来影响肺对变应原的特异性应答。在这 我们将1）使用一种创新的方法来确定过敏原如何通过IL-10支持Blimp-1和Th 2细胞， 将无偏基因表达分析与组织中的空间定位相结合以鉴定IL-10的技术 在肺和淋巴结中产生细胞以及它们与表达Blimp-1的T细胞的关系。另外我们 将2）进行scRNAseq和scATACseq，以确定在 过敏性致敏作用影响过敏原攻击后的免疫应答。我们希望这些研究能够确定 肺引流淋巴结中T细胞引发的基本早期步骤，以响应肺源性过敏原， 这表明处于稳态的组织特异性环境信号可以影响随后的免疫反应， 对抗原攻击的应答驱动独特的T细胞分化途径。此外，我们的公正 这些方法有可能阐明早期T细胞引发途径的空间定位， 鉴定促进对过敏原的2型免疫的新介质。因此，这些研究将有一个 对未来研究的根本影响，可以确定潜在的治疗靶点，用于治疗 过敏性哮喘