Lung dopaminergic nerves facilitate the establishment of TH2 resident memory cells in early life

Abstract

Allergic asthma develops from allergen exposure in early childhood and progresses into adulthood. The central mediator of progressive allergic asthma is allergen-specific, TH2-resident memory cells (TRMs). Although the crosstalk between nerves and immune cells plays an established role in acute allergic inflammation, whether nerves facilitate the establishment of TH2-TRMs in the immature lung following early life allergen exposure is unknown. The aim of this study was to identify nerve-derived signals that act in TH2 effector cells to regulate the tissue residency in the immature lung. Following neonatal allergen exposure, allergen-specific TH2-TRMs were tracked temporally and spatially in relationship to developing sympathetic nerves in the lung. Functional mediators of dopamine signaling in the establishment of TH2-TRMs were identified by invitro bulk RNA-sequencing of dopamine-treated TH2 cells followed by invivo assessment of candidate genes using adoptive transfer of TH2 cells with viral gene knockdown. This study found that sympathetic nerves produce dopamine and reside in proximity to TH2 effector cells during the contraction phase following neonatal allergen exposure. Dopamine signals via DRD4 on TH2 cells to elevate IL2RA and epigenetically facilitate type 2 cytokine expression. Blockade of dopamine-DRD4 signaling following neonatal allergen exposure impairs lung residence of TH2 cells and ameliorates anamnestic inflammation in adults. These results demonstrate that maturing sympathetic nerves enable a dopamine-enriched lung environment in early life that promotes the establishment of allergen-specific TH2-TRMs. The dopamine-DRD4 axis may provide a therapeutic target to modify allergic asthma progression from childhood to adulthood.