Retinoic acid regulates the development of a gut homing precursor for intestinal dendritic cells

The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that retinoic acid also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-μDCs). Pre-μDCs express the gut trafficking receptor α4β7 and home preferentially to the intestines. They develop in the bone marrow, can differentiate into CCR9(+) plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103(+) intestinal cDCs. Generation of pre-μDCs in vivo in the bone marrow or in vitro is regulated by RA and retinoic acid receptor α signaling. The frequency of pre-μDCs is reduced in vitamin A-deficient animals and in animals treated with retinoic acid receptor inhibitors. The results define a novel vitamin A-dependent, retinoic-acid-regulated developmental sequence for dendritic cells and identify a targeted precursor for CD103(+) cDCs in the gut.