Does age matter for the development of pathogenic T helper 2 resident memory cells in the lung?

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.