PROJECT SUMMARY
Allergic asthma is a chronic inflammatory disease that often progresses from childhood to adulthood.
Approximately 8% of the world population suffer from allergic asthma, making it one of the most common
respiratory diseases. Allergic asthma is characterized by recurrent type 2 inflammation, mucus
hyperplasia, and airway hyperreactivity. Current treatment strategies aim to temporally alleviate the
symptoms of asthma attack and have no beneficial effect on disease progression. Recent studies have
identified pathogenic T helper 2 resident memory cells in the lung (Th2-TRMs) as the critical driver of
recurrent exacerbations in allergic asthma and thus, an appealing therapeutic target. Considering that
allergic asthma has an early age onset, pathogenic Th2-TRMs likely are established since early
childhood. However, pathogenic Th2-TRMs in the immature lung have not been characterized, at least
in part, due to technical difficulties of accessing the lung tissue in young children with allergic asthma. In
addition, a majority of allergic asthma models are generated using adult animals. As such, how
pathogenic Th2-TRMs are established following early life allergen exposure is unknown. Here, employing
two neonatal mouse models of allergic inflammation that reproduce the saline features of progressive
allergic asthma in patients, we provide evidence that age is a critical factor in the lung Th2-TRM program.
In Preliminary Studies, we show that Th2 effector cells induced by neonatal allergen exposure are more
readily to become resident memory cells than the counterparts induced in adults. We also find that
environmental signals unique to the immature lung, such as nerve-derived dopamine, promote residency
of Th2 TRMs. In addition to our preliminary results, the type 2 bias of immature CD4+ T cells and dendritic
cells is well-characterized and may also contribute to the phenotype and the function of allergen-specific
Th2-TRMs established in early life. Based on these findings, we hypothesize that immaturity of CD4+ T
cells and the lung environment in early life endows an age-related Th2-TRM program to promote
residency and anamnestic allergic inflammation. To test this hypothesis, we will compare Th2-TRMs
generated following allergen exposure in neonatal and adult mice to identify differences in the phenotype
and the function of allergen-specific Th2 TRMs with age. To what extent the immaturity of T cells and the
developing lung environment contribute to age-related Th2-TRM phenotypes will also be assessed. The
results of our proposed studies will identify molecular mediators unique to the early life Th2-TRM
program. These mediators can be studied in future R01 projects as therapeutic targets to modify the
progression of allergic asthma from childhood to adulthood.
