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

点击翻译按钮获取中文摘要

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.