Abstract
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-μDCs). Pre-μDCs express the gut trafficking receptor α4β7 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-μDCs in vivo in the BM or in vitro is regulated by RA and RA receptor α (RARα) signaling. The frequency of pre-μDCs 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens, CD / metabolism
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Dendritic Cells / cytology
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Dendritic Cells / drug effects*
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Dendritic Cells / metabolism*
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Immunologic Factors / pharmacology*
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Immunophenotyping
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Integrin alpha Chains / metabolism
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Integrin alpha4 / metabolism
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism
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Mice
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Peyer's Patches / drug effects
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Peyer's Patches / immunology
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Peyer's Patches / metabolism
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Phenotype
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Receptors, CCR / metabolism
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Stem Cells / cytology
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Stem Cells / drug effects*
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Stem Cells / metabolism*
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Tretinoin / pharmacology*
Substances
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Antigens, CD
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CC chemokine receptor 9
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Immunologic Factors
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Integrin alpha Chains
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Receptors, CCR
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alpha E integrins
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Integrin alpha4
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Tretinoin