Skin-Specific CD301b⁺ Dermal Dendritic Cells Drive IL-17-Mediated Psoriasis-Like Immune Response in Mice

Conventional dendritic cells (cDCs) are composed of heterogeneous subsets commonly arising from dendritic cell (DC)-committed progenitors. A population of CD301b-expressing DCs has recently been identified in non-lymphoid barrier tissues such as skin. However, whether CD301b⁺ DCs in the skin represent an ontogenetically unique subpopulation of migratory cDCs has not been fully addressed. Here, we demonstrated that CD301b⁺ dermal DCs were distinct subpopulation of FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent CD11b⁺ cDC2 lineage, which required an additional GM-CSF cue for the adequate development. Although the majority of lymphoid-resident cDC2 lacked CD301b expression, dermal migratory cDC2 contained a substantial fraction of CD301b⁺ subset. Similar to CD301b^- population, CD301b⁺ dermal DC development was closely regulated by FLT3 signaling, suggesting their common origin from FLT3L-responsive cDC progenitors. However, FLT3L-driven cDC progenitor culture was not sufficient, but additional GM-CSF treatment was required to produce CD301b⁺ cDC2. In vivo development of CD301b⁺ cDC2 was significantly augmented by exogenous GM-CSF, while the repopulation of CD301b⁺ dermal cDC2 was abrogated by GM-CSF neutralization. Functionally, CD301b⁺ cDC2 was capable of producing a high level of IL-23, and the depletion of CD301b⁺ cDC2 effectively prevented IL-17-mediated psoriasiform dermatitis. Therefore, our findings highlight the differentiation program of a distinct CD301b⁺ dermal cDC2 subset in the skin and its involvement in psoriatic inflammation.