Abstract

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88(-)CD1c(+)CD163(+) DCs (called DC3s) as immediate precursors of inflammatory CD88(-)CD14(+)CD1c(+) CD163(+)Fc epsilon RI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro, DC3s displayed a distinctive ability to prime CD8(+) T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor beta (TGF-beta) signaling. In vivo, DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8(+)CD103(+)CD69(+) tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity.