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: 10301436
• 负责人: Amanda Catherine Poholek
• 金额: $ 18.6万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301436
• 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; Lung Inflammation; Mediating; Mediator of activation protein; Modeling; Mus; Myeloid Cells; Pathogenesis; Pathway interactions; Patients; Play; Production; 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.

项目总结 过敏原是一类无害的环境抗原，可驱动不适当的炎症免疫。 易感个体的反应通常以辅助T细胞产生2型细胞因子为特征 (Th2)。吸入屋尘螨等过敏原会导致肺部过敏性炎症，但准确地说 过敏原如何驱动肺组织中的2型免疫反应尚不清楚。我们之前已经 Blimp-1在吸入性肺内Th2细胞分化中起中心作用 过敏原。然而，皮下注射相同的过敏原不需要Blimp-1来治疗 Th2细胞的形成，提示进入的途径和驻留的组织特异性免疫细胞决定 Blimp-1在Th2细胞分化中的必要性我们发现，在对吸入性抗原的反应中，IL-10 在Th2细胞中促进Blimp-1的关键细胞因子。BLIMP-1通过抑制Bcl6发挥作用，而Bcl6本身就是一个强有力的抑制因子 与Th2细胞相关的规范转录因子GATA3。基于这些数据，我们建议 在T细胞过程中，肺细胞从局部组织环境向淋巴结引流的独特信号 启动通过促进Blimp-1和2型免疫来影响肺对变应原的特异性反应。在这 我们将1)确定变应原如何通过IL-10支持Blimp-1和Th2细胞 结合无偏基因表达分析和组织中的空间定位来识别IL-10的技术 肺和淋巴结中产生的细胞及其与表达Blimp-1的T细胞的关系。此外，我们 将2)执行scRNAseq和scATACseq以确定特定于肺的环境是如何在 过敏性致敏作用影响过敏原攻击时的免疫反应。我们希望这些研究能够确定 肺引流淋巴结内T细胞启动以应对肺源性变应原的基本早期步骤 证明处于动态平衡的组织特异性环境信号可以塑造随后的免疫 对抗原的反应挑战驱动独特的T细胞分化途径。另外，我们不偏不倚的 这些方法既有可能阐明早期T细胞启动途径的空间位置，也有可能 确定促进对过敏原的2型免疫的新介质。因此，这些研究将有一个 对可能确定潜在治疗靶点的未来研究的基本影响 过敏性哮喘。