title: Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells.
abstract: The vitamin A metabolite all-trans retinoic acid (RA) is an important determinant of intestinal immunity. RA primes dendritic cells (DCs) to express CD103 and produce RA themselves, which induces the gut-homing receptors α4β7 and CCR9 on T cells and amplifies transforming growth factor (TGF)-β-mediated development of Foxp3(+) regulatory T (Treg) cells. Here we investigated the effect of RA on human DCs and subsequent development of T cells. We report a novel role of RA in immune regulation by showing that RA-conditioned human DCs did not substantially enhance Foxp3 but induced α4β7(+) CCR9(+) T cells expressing high levels of interleukin (IL)-10, which were functional suppressive Treg cells. IL-10 production was dependent on DC-derived RA and was maintained when DCs were stimulated with toll-like receptor ligands. Furthermore, the presence of TGF-β during RA-DC-driven T-cell priming favored the induction of Foxp3(+) Treg cells over IL-10(+) Treg cells. Experiments with naive CD4(+) T cells stimulated by anti-CD3 and anti-CD28 antibodies in the absence of DCs emphasized that RA induces IL-10 in face of inflammatory mediators. The data thus show for the first time that RA induces IL-10-producing Treg cells and postulates a novel mechanism for IL-10 in maintaining tolerance to the intestinal microbiome.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Bakdash
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L T C
authors.initials: LT
authors.lastname: Vogelpoel
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: T M M
authors.initials: TM
authors.lastname: van Capel
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Kapsenberg
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E C
authors.initials: EC
authors.lastname: de Jong
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D064307:Microbiota; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D018168:Receptors, Retinoic Acid; C091367:alpha E integrins; D016753:Interleukin-10; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase