Biased Generation and In Situ Activation of Lung Tissue-Resident Memory CD4 T Cells in the Pathogenesis of Allergic Asthma

Asthma is a chronic inflammatory disease mediated by allergen-specific CD4 T cells that promote lung inflammation through recruitment of cellular effectors into the lung. A subset of lung T cells can persist as tissue-resident memory T cells (TRMs) following infection and allergen induction, although the generation and role of TRM in asthma persistence and pathogenesis remain unclear. In this study, we used a mouse model of chronic exposure to intranasal house dust mite ( HDM) extract to dissect how lung TRMs are generated and function in the persistence and pathogenesis of allergic airway disease. We demonstrate that both CD4 + and CD8 + T cells infiltrate into the lung tissue during acute HDM exposure; however, only CD4(+) TRMs, and not CD8 + TRMs, persist long term following cessation of HDM administration. Lung CD4(+) TRMs are localized around airways and are rapidly reactivated upon allergen re-exposure accompanied by the rapid induction of airway hyperresponsiveness independent of circulating T cells. Lung CD4(+) TRM activation to HDM challenge is also accompanied by increased recruitment and activation of dendritic cells in the lungs. Our results indicate that lung CD4(+) TRMs can perpetuate allergen-specific sensitization and direct early inflammatory signals that promote rapid lung pathology, suggesting that targeting lung CD4(+) TRMs could have therapeutic benefit in alleviating recurrent asthma episodes.