Lung-resident memory CD4+ T cells are dependent on Batf3

Abstract Tissue-resident memory cells contribute to allergen-induced inflammation and airway hyperresponsiveness, but relatively little is known of the cellular and molecular mechanisms underlying the accumulation of these cells in the lung. Here, we show that allergen-specific CD4+ resident memory T cells are virtually absent in lungs of mice lacking Batf3, a transcription factor required for the development of type 1 lung dendritic cells (cDC1). These animals become sensitized to inhaled allergens and display normal responses in a short-term house dust mite–dependent model of asthma. However, they have strongly reduced airway inflammation and weak airway hyperresponsiveness in a similar, but long-term model of asthma. Single-cell RNA sequencing revealed that Batf3-deficient mice lack a subset of lung-resident CD4+ T cells characterized by expression of the chemokine receptor–encoding gene, Cxcr6. Together, these data show that Batf3 promotes the development of CD4+ resident memory T cells and thus allergic responses to inhaled allergens.