Batf3-dependent type 1 dendritic cells drive the accumulation of lung resident memory CD4+ T cells

Tissue resident memory cells have recently emerged as a critically important cell type for both protective and pathogenic immune responses. In particular, these cells are required for allergen-induced airway hyperresponsiveness in animal models of allergic asthma. However, relatively little is known of the cellular and molecular mechanisms underlying the accumulation of these cells in the lung. Here, using gene targeted mice and MHC class II tetramers specific to clinically relevant house dust mite allergen, we show that allergen-specific resident memory CD4+ T cells are virtually absent in mice lacking Batf3, a transcription factor required for the development of type 1 lung dendritic cells. As a result, these animals display markedly reduced airway inflammation and very weak airway hyperresponsiveness in a house dust mite model of allergic 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 suggest that blocking the development or function of allergen-specific resident memory CD4+ T cells might be an effective approach to treat patients with allergic asthma. Overall design: Wild type and Batf3-deficient mice were sensitized twice with house dust mite allergens, then rested for 5 weeks. Immediately prior to harvest, the animals received intravenous injections of anti-CD45 antibodies to label circulating leukocytes. Following euthanasia, lungs were excised and digested, and CD45 positive and CD45 negative T cells from both mouse strains separately purified by flow cytometry. The cells were subjected to single cell RNA sequencing and the data analyzed.