Generation and transcriptional programming of intestinal dendritic cells: Essential role of retinoic acid

The vitamin A metabolite retinoic acid (RA) regulates adaptive immunity in the intestines, with well-characterized effects on IgA responses, Treg induction and gut trafficking of T and B effector cells. It also controls the generation of cDC precursors in the bone marrow and regulates cDC subset representation, but its roles in the specialization of intestinal cDC subsets is understudied. Here we show that RA acts cell-intrinsically in developing gut-tropic pre-mucosal DC (pre-μDC) to effect the differentiation and drive the specialization of intestinal CD103+CD11b− (cDC1) and of CD103+CD11b+ (cDC2). Systemic deficiency or DC-restricted antagonism of RA signaling resulted in altered phenotypes of intestinal cDC1 and cDC2, and reduced numbers of cDC2. Effects of dietary deficiency were most apparent in the proximal small intestine, and were rapidly reversed by reintroducing vitamin A. In cultures of pre-μDC with Flt3L and GM-CSF, RA induced cDC with characteristic phenotypes of intestinal cDC1 and cDC2 by controlling subset-defining cell surface receptors, regulating subset-specific transcriptional programs, and suppressing proinflammatory NF-κB-dependent gene expression. Thus RA is required for transcriptional programming and maturation of intestinal cDC, and with GM-CSF and Flt3L provides a minimal environment for in vitro generation of intestinal cDC1- and cDC2-like cDC from specialized precursors.