title: Human CD1c⁺ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D₃.
abstract: All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D₃ (VD₃) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD₃. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD₃ in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Takayuki
authors: T
authors: Sato
authors: Toshio
authors: T
authors: Kitawaki
authors: Haruyuki
authors: H
authors: Fujita
authors: Makoto
authors: M
authors: Iwata
authors: Tomonori
authors: T
authors: Iyoda
authors: Kayo
authors: K
authors: Inaba
authors: Toshiaki
authors: T
authors: Ohteki
authors: Suguru
authors: S
authors: Hasegawa
authors: Kenji
authors: K
authors: Kawada
authors: Yoshiharu
authors: Y
authors: Sakai
authors: Hiroki
authors: H
authors: Ikeuchi
authors: Hiroshi
authors: H
authors: Nakase
authors: Akira
authors: A
authors: Niwa
authors: Akifumi
authors: A
authors: Takaori-Kondo
authors: Norimitsu
authors: N
authors: Kadowaki
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology / Q000378:metabolism*; D002762:Cholecalciferol / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050697:Retinal Dehydrogenase / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D002762:Cholecalciferol; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase