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

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.

Grant Number: 5R01HL154549-04
NIH Institute/Center: NIH
Principal Investigator: Xingbin Ai