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

Abstract

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 CD3011D(+) DCs in the skin represent an ontogenetically unique subpopulation of migratory cDCs has not been fully addressed. Here, we demonstrated that CD3011D(+) dermal DCs were distinct subpopulation of FMS-like tyrosine kinase 3 ligand (FLT3L) dependent CD111D(+) 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 CD3011D(+) subset. Similar to CD301b- population, CD3011D(+) 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 CD3011D(+) cDC2. In vivo development of CD3011D(+) cDC2 was significantly augmented by exogenous GM-CSF, while the repopulation of CD3011D(+) dermal cDC2 was abrogated by GM-CSF neutralization. Functionally, CD3011D(+) cDC2 was capable of producing a high level of IL-23, and the depletion of CD3011D(+) cDC2 effectively prevented IL-17 mediated psoriasiform dermatitis. Therefore, our findings highlight the differentiation program of a distinct CD3011D(+) dermal cDC2 subset in the skin and its involvement in psoriatic inflammation.