CD11b⁺ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b⁺ DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C⁺, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C⁺Ly-6A/E⁺ cDC2 to mature Ly-6C^-CD301b⁺ lung resident cDC2 lacking Ccr7 expression, which then further mature into CD200⁺ migratory cDC2 expressing Ccr7. Partially mature Ly-6C⁺Ly-6A/E^-CD301b^- cDC2, which express Il1b, promote Th17 differentiation. By contrast, CD200⁺ mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.