title: Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells.
abstract: BACKGROUND
  The vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression is priming of dendritic cells (DCs) to induce regulatory T (Treg) cells.
  
  
  OBJECTIVE
  Currently, there is confusion about the phenotype of VitD3-induced Treg cells and the DC-derived molecules driving their development. We investigated Treg cell induction after VitD3 priming of 2 distinct skin DC subsets: Langerhans cells (LCs) and dermal dendritic cells (DDCs).
  
  
  METHODS
  LCs and DDCs primed with VitD3 were cocultured with allogeneic naive T cells. The phenotype and function of the DCs and induced T cells were analyzed.
  
  
  RESULTS
  Both VitD3-primed DC subtypes induced T cells with regulatory activity. Unexpectedly, whereas the Treg cell populations generated by VitD3-primed LCs were CD25(hi)CD127(lo) forkhead box protein 3 (Foxp3)-positive cells, which meet the criteria of classical inducible Treg cells, the T cells developing in response to VitD3-primed DDCs were Foxp3(-) T(R)1 cells expressing IL-10. Inhibition experiments revealed that LC-derived TGF-β is a key factor in the induction of Foxp3(+) Treg cells, whereas DDC-derived IL-10 is important for the induction of IL-10(+) T(R)1 cells.
  
  
  CONCLUSIONS
  Thus we report the novel finding that distinct but closely related DC subsets are differentially programmed by VitD3 to support development of either TGF-β-dependent Foxp3(+) Treg cells or IL-10-dependent IL-10(+) Treg cells.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Angelic M G
authors.initials: AM
authors.lastname: van der Aar
authors.forename: Darya S
authors.initials: DS
authors.lastname: Sibiryak
authors.forename: Ghaith
authors.initials: G
authors.lastname: Bakdash
authors.forename: Toni M M
authors.initials: TM
authors.lastname: van Capel
authors.forename: Hanneke P M
authors.initials: HP
authors.lastname: van der Kleij
authors.forename: Dirk-Jan E
authors.initials: DJ
authors.lastname: Opstelten
authors.forename: Marcel B M
authors.initials: MB
authors.lastname: Teunissen
authors.forename: Martien L
authors.initials: ML
authors.lastname: Kapsenberg
authors.forename: Esther C
authors.initials: EC
authors.lastname: de Jong
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D007519:Isoantigens; D007801:Langerhans Cells / Q000145:classification / Q000187:drug effects* / Q000276:immunology*; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D007519:Isoantigens; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D002117:Calcitriol