Abstract
Abstract Allergic asthma is an inflammatory disease of the airways associated with T helper (Th)2-driven eosinophilia and Th17-directed neutrophilia. Although eosinophilic asthma generally responds well to inhaled glucocorticoids, neutrophilic asthma does not, and new therapies are needed for this disease subtype. A consensus DC subset in the lung that strongly promotes Th17 responses to inhaled allergens has remained elusive, as some groups have reported that CD103+ DCs (DC1) promote Th17 differentiation, whereas other groups have attributed this function to CD11bhi DCs (DC2). We hypothesized that this apparent discrepancy might be due to the heterogeneity of lung CD11b+ DCs and therefore used mass cytometry (CyTOF) to study these cells following allergic sensitization through the airway. We identified a novel CD11b+ APC that was recruited to the inflamed airways of mice following their inhalation of house dust extracts. These cells were bona fide DCs, as they were FLT3L-dependent, expressed Zbtb46, and formed dendrites. Bulk RNA-seq analysis of these DCs revealed that their transcriptome was similar to, yet distinct from, that of conventional DC2s. Although the novel DCs promoted only weak Th2 differentiation, they drove robust Th17 differentiation. Single cell RNA-sequencing of total lung CD11bhi DCs revealed seven distinct clusters, two of which co-expressed both Tgfb1 and Il1b. Pseudotime analysis suggested a progression from an immature form of these cells to a more mature form. Together, these findings identify a novel DC population (DC3) in the lung that potently stimulates Th17 responses to inhaled allergens.
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