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 RA also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-mu DCs). Pre-mu DCs express the gut trafficking receptor alpha 4 beta 7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into CCR9(+) plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103(+) intestinal cDCs. Generation of pre-mu DCs in vivo in the BM or in vitro is regulated by RA and RA receptor alpha (RAR alpha) signaling. The frequency of pre-mu DCs is reduced in vitamin A-deficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103(+) cDCs in the gut.