IL-9-secreting tissue-resident memory T cells in allergic airway disease

过敏性气道疾病中分泌 IL-9 的组织驻留记忆 T 细胞

• 批准号: 9760273
• 负责人: Benjamin Ulrich
• 金额: $ 3.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760273
• 关键词: Abbreviations; Acute; Address; Affect; Age; Allergens; Allergic; Allergic Disease; Allergic inflammation; American; Americas; Antigens; Asthma; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; Complement Factor B; Data; Development; Disease; Effector Cell; Exposure to; Foundations; Goals; Green Fluorescent Proteins; Health Care Costs; Human; Hypersensitivity; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-9; Interleukins; Intervention; Knock-out; Lung; Mediating; Mediator of activation protein; Memory; Modeling; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Prevalence; Process; Production; Race; Recurrence; Reporter; Rest; Structure of parenchyma of lung; Symptoms; T memory cell; T-Lymphocyte; Testing; Th2 Cells; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; United States; allergic airway disease; allergic airway inflammation; cost; cytokine; demographics; diphtheria toxin receptor; effector T cell; in vivo; in vivo Model; inflammatory lung disease; memory recall; novel; productivity loss; recruit; response; sex; targeted treatment; transcription factor

PROJECT SUMMARY Asthma is a chronic inflammatory lung disease for which there is no cure. Allergen specific CD4 T helper (Th) cells mediate processes which characterize the majority of asthma pathogenesis. After encountering antigen, memory cells can circulate or reside in non-lymphoid tissues providing antigen specific secondary responses. This proposal focuses on the tissue-resident memory (Trm) T cells that remain tissue-bound. In our preliminary data we identified lung Trm cells in a model of allergic airway disease that produce a polarized cytokine profile including the production of IL-9 similar to Th9 cells. We have further characterized in a chronic exposure to allergen and in a memory recall response that these Th9-like Trm cells are maintained in the tissue and provide a robust secondary response. In the single Aim, we will use parallel approaches to examine the development and function of IL-9-secreting Trm cells. In the first sub-aim, we will use Th9 transcription factor-deficient mice to examine differences in Trm cell development. In the second sub-aim, we will examine IL-9 effector function in recall responses. Lastly in the third sub-aim, we will determine if IL-9-secreting Trm cells are sufficient to mediate allergic airway inflammation. Together this Aim will explore the functionality of a pro-allergic subset sharing a phenotype similar to what has been associated with allergic disease is patients. These studies will define novel contributions of CD4 Trm T cells to allergic inflammation in the lung and potentially identify new pathways as targets for therapeutic intervention in persistent asthma.

项目总结 哮喘是一种慢性炎症性肺部疾病，目前尚无治愈方法。变应原特异性CD4T辅助细胞(Th) 细胞介导的过程是哮喘发病的主要特征。在遇到抗原后， 记忆细胞可以循环或驻留在非淋巴组织中，提供抗原特异性的次级反应。 这项建议关注的是仍与组织结合的组织驻留记忆(Trm)T细胞。在我们的预赛中 我们在过敏性呼吸道疾病模型中发现了肺Trm细胞，该细胞产生两极分化的细胞因子谱 包括产生类似Th9细胞的IL-9。我们的进一步特征是长期接触到 在记忆回忆反应中，这些Th9样Trm细胞在组织中保持并提供 一个强有力的二次反应。在单一目标中，我们将使用并行方法来检查发展 和分泌IL-9的Trm细胞的功能。在第一个子目标中，我们将使用Th9转录因子缺陷小鼠 以检验Trm细胞发育的差异。在第二个子目标中，我们将检查IL-9效应器的功能 在召回反应中。最后，在第三个子目标中，我们将确定分泌IL-9的Trm细胞是否足以 介导过敏性呼吸道炎症。这一目标将共同探索亲过敏亚群的功能 与过敏性疾病相关的表型相似的是患者。这些研究将 确定CD4Trm T细胞对肺部变态反应性炎症的新贡献，并有可能确定新的 通路作为持续性哮喘治疗干预的靶点。