title: Generation and transcriptional programming of intestinal dendritic cells: essential role of retinoic acid.
abstract: 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 conventional dendritic cell (cDC) precursors in the bone marrow and regulates cDC subset representation, but its roles in the specialization of intestinal cDC subsets are understudied. Here we show that RA acts cell intrinsically in developing gut-tropic pre-mucosal dendritic cell (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 granulocyte-macrophage colony-stimulating factor (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 nuclear factor-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.
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Program of Immunology, Stanford University School of Medicine, Stanford, California, USA.|Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bscheider
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lahl
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Butcher
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015398:Signal Transduction; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D039481:CD11b Antigen; D039001:Integrin alpha Chains; D008565:Membrane Proteins; C091367:alpha E integrins; C084881:flt3 ligand protein; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor