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

项目摘要 哮喘是一种无法治愈的慢性炎症性肺部疾病。变应原特异性CD 4辅助性T细胞（Th） 细胞介导的过程表征了大多数哮喘发病机理。遇到抗原后， 记忆细胞可以循环或驻留在非淋巴组织中，提供抗原特异性次级应答。 该提案的重点是保持组织结合的组织驻留记忆（Trm）T细胞。在我们的初步调查中 我们在过敏性气道疾病模型中鉴定了肺Trm细胞， 包括产生类似于Th 9细胞的IL-9。我们进一步描述了慢性暴露于 过敏原和记忆回忆反应，这些Th 9样Trm细胞维持在组织中，并提供 一个强有力的二级反应在单一目标中，我们将使用并行方法来检查开发 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Th 9转录因子缺陷小鼠 以检查Trm细胞发育的差异。在第二个子目标中，我们将检查IL-9效应器功能， in recall召回responses响应.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 介导过敏性气道炎症。这一目标将共同探讨促过敏亚组的功能 患者具有与变应性疾病相关的表型相似的表型。这些研究将 定义了CD 4 Trm T细胞对肺部过敏性炎症的新贡献，并可能发现新的 作为持续性哮喘治疗干预的靶点。

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.