Age-related mechanisms of T helper 2 memory in the early lung

项目摘要 过敏性哮喘是最常见的慢性气道疾病之一，通常从婴儿期开始发展， 从幼年到成年目前的治疗针对拮抗炎症和支气管炎。 收缩。尽管这些疗法被广泛使用，但它们对减缓癌症的发展没有任何有益的作用。 过敏性哮喘的进展。回忆性过敏反应的中心介质是过敏原特异性的，T 辅助2驻留记忆细胞（Th 2-TRM）。因此，靶向建立过敏原特异性Th 2-TRM 在生命早期暴露后，提供了调节和阻止进行性过敏性哮喘的机会。 然而，Th 2-TRM如何在早期肺中建立从未被研究过。为了解决这个关键问题， 在进行性变应性哮喘的发病机制中，我们研究了过敏原 在生命早期的暴露和对气道炎症的长期影响。我们的研究重点是沟通 交感神经和出生后发育中的肺中的CD 4 + T细胞之间的关系。到目前为止，我们的出版和 初步研究已经确定了神经源性多巴胺在过敏性哮喘易感性中的重要作用 在早期生活和成人的回忆过敏反应。我们发现多巴胺信号通过T细胞特异性的 DRD 4受体通过激活转录因子和表观遗传调节剂促进Th 2-TRM表型 Th 2细胞。有趣的是，交感神经随着年龄的增长转变为肾上腺素能表型。因此，神经- 衍生的多巴胺以与年龄相关的方式起作用以促进Th 2记忆。考虑到多巴胺的关键作用 在早期肺中Th 2-TRM的建立中，我们研究了出生后 交感神经我们发现了与年龄相关的神经生长因子（NGF）和脑- 脑源性神经营养因子（BDNF）与多巴胺能向肾上腺素能的转变有关， 交感神经基于这些初步发现，我们提出了核心假设：多巴胺 促进建立过敏原特异性，Th 2-TRM在早期肺;多巴胺能， 交感神经的肾上腺素能转换是由年龄相关的NGF和BDNF水平降低引起的。 这些假设将通过以下三个具体目标进行检验。目标1将确定以下方面的具体作用： 早期过敏原暴露后过敏原特异性Th 2-TRM的丰度和功能中的多巴胺 生活目的2将确定多巴胺信号的功能介质在Th 2-TRM表型。目标3将决定 NGF和BDNF在肺中交感神经支配和变应原特异性Th 2-TRM中的作用。值得注意的是， 临床研究和GWAS已经报道了NGF和BDNF水平与过敏性疾病之间的正相关性。 哮喘综上所述，我们提出的研究将提供深入了解建立的Th 2-TRM中， 早期肺，并确定从儿童到成年的进行性哮喘干预的分子靶点。

PROJECT SUMMARY Allergic asthma is one of the most common, chronic airway diseases that often progresses from infancy and early childhood into adulthood. Current therapies are directed at antagonizing inflammation and bronchial constriction. Despite their widespread use, these therapies have no beneficial effect on slowing down the progression of allergic asthma. The central mediator of anamnestic allergic responses is allergen-specific, T helper 2 resident memory cells (Th2-TRMs). As such, targeting the establishment of allergen-specific, Th2-TRMs following early life exposure provides an opportunity to modulate and impede progressive allergic asthma. However, how Th2-TRMs are established in the early lung has never been studied. To address this critical issue in the pathogenesis of progressive allergic asthma, we have investigated the causal link between allergen exposure in early life and the long-term effect on airway inflammation. Our study focuses on the communication between sympathetic nerves and CD4+ T cells in the postnatal, developing lung. So far, our published and preliminary studies have identified a significant role of nerve-derived dopamine in susceptibility to allergic asthma in early life and anamnestic allergic responses in adults. We show that dopamine signals through a T cell-specific DRD4 receptor to promote Th2-TRM phenotypes by activating transcriptional factors and epigenetic modulators in Th2 cells. Interestingly, sympathetic nerves transition into an adrenergic phenotype with age. Therefore, nerve- derived dopamine operates in an age-related manner to promote Th2 memory. Given the critical role of dopamine in the establishment of Th2-TRMs in the early lung, we have investigated the postnatal development of sympathetic nerves. We found an age-related reduction in the levels of nerve growth factor (NGF) and brain- derived neurotrophic factor (BDNF) that was associated with the dopaminergic-to-adrenergic transition of sympathetic nerves. Empowered by these preliminary findings, we propose the central hypotheses: dopamine promotes the establishment of allergen-specific, Th2-TRMs in the early lung; the dopaminergic-to- adrenergic transition of sympathetic nerves is caused by age-related reduction in NGF and BDNF levels. These hypotheses will be tested by the following three specific aims. Aim 1 will define the specific role of dopamine in the abundance and the function of allergen-specific, Th2-TRMs following allergen exposure in early life. Aim 2 will identify functional mediators of dopamine signaling in Th2-TRM phenotypes. Aim 3 will determine the role of NGF and BDNF in sympathetic innervation and allergen-specific, Th2-TRMs in the lung. Of note, clinical studies and GWAS have reported positive correlation between the levels of NGF and BDNF and allergic asthma. Taken together, our proposed studies will provide insights into the establishment of Th2-TRMs in the early lung and identify molecular targets for the intervention of progressive asthma from childhood to adulthood.