Diverse developmental pathways of lymphoid conventional dendritic cells with distinct tissue distribution and function.

Conventional dendritic cells (cDCs) regulate adaptive immunity. Although most cDCs are of myeloid origin (M-cDCs), some cDCs originate from pro-plasmacytoid DCs (pro-pDCs) via pDC-like cells [lymphoid cDCs (L-cDCs)]. Using lymphoid progenitor-tracking systems, we report tissue segregation, a unique differentiation pathway, and the functions of L-cDCs. Notably, L-cDC2s are predominantly distributed in barrier tissues such as the lungs and skin. Single-cell RNA-sequencing analysis revealed the enrichment of lymphocyte signature genes in L-cDCs. We identified lymphocyte-primed cDC precursors, which are distinct from pDC-like cells, as sources of L-cDCs. Compared with M-cDC2s, L-cDC2s weakly primed T cells under low-dose antigen stimulation and preferentially promoted T helper 2 (T(H)2) differentiation under sufficient antigenic stimulation. These results suggest the diverse developmental pathways of L-cDCs and imply the contribution of L-cDCs to tolerance and hyperresponses to T(H)2-related antigens in barrier tissues.