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Angelic M. G. van der Aar, PhD, Darya S

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1 Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells 
Angelic M.G. van der Aar, PhD, Darya S. Sibiryak, PhD, Ghaith Bakdash, MSc, Toni M.M. van Capel, Ing, Hanneke P.M. van der Kleij, PhD, Dirk-Jan E. Opstelten, PhD, Marcel B.M. Teunissen, PhD, Martien L. Kapsenberg, PhD, Esther C. de Jong, PhD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 6, Pages e7 (June 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 VitD3 priming hampers the ability of DDCs and LCs to promote T-cell proliferation. Proliferation of allogeneic naive CD4+ T cells stimulated by DDCs or LCs that were primed with MF (TNF-α/IL-1β) in the presence or absence of 2.5 μM VitD3 is shown. Data are shown as means ± SDs of triplicates of 1 representative experiment (n = 5). ∗P < .05. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 VitD3-primed DDCs and LCs induce regulatory activity in CD4+ T cells. Proliferation of target cells in the presence of T cells stimulated by in vitro–generated MF/VitD3-primed DDCs or LCs (A), different ratios of T cells stimulated by in vitro–generated MF/VitD3-primed DDCs or LCs (B), or T cells stimulated by skin-derived MF/VitD3-primed DDCs or LCs (C). Data are shown as means ± SDs of 5 (Fig 2, A and C) or 2 (Fig 2, B) independent experiments. ∗P < .05. ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 VitD3 inhibits TH1 the cell–inducing capacity of DDCs and LCs. IFN-γ and IL-4 production by CD4+ T cells activated by MF/VitD3-primed DDCs and LCs is shown. The graph shows means ± SDs of 5 independent experiments. ∗P < .05. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 VitD3-primed LCs induce Foxp3+ T cells, whereas VitD3-primed DDCs do not. A, Representative Foxp3 and CD127 expression by CD4+ T cells stimulated by DDCs and LCs primed with MF/2.5 μM VitD3. B, Induction of CD127−Foxp3+ T cells by DDCs and LCs primed with different concentrations of VitD3. C, Kinetics of Foxp3 expression of T cells stimulated with VitD3-primed DDCs and LCs. D, Induction of CD127−Foxp3+ T cells by skin-derived DDCs and LCs primed with 0.5 μM VitD3. Data show a representative experiment (Fig 4, A, n = 12; Fig 4, C, n = 3) or the mean ± SD of 3 independent experiments (Fig 4, B and D). ∗P < .05. ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 VitD3-primed DDCs induce IL-10–producing Treg cells. A, T cells stimulated with MF and MF/VitD3-primed DDCs and LCs were gated on CD4 and analyzed for IL-10 secretion by means of flow cytometry. Data show 1 representative experiment of 5. B, IL-10 in the supernatants of T cells induced by MF/VitD3-primed DDCs and LCs. C, IL-10 production by T cells induced by skin-derived DDCs and LCs primed with 0.5 μM VitD3. Results are a representative experiment of 5 (Fig 5, A) or the mean ± SD of 3 (Fig 5, B) or 2 (Fig 5, C) independent experiments. ∗P < .05. ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Effects of VitD3 on the phenotype of DDCs and LCs. CD14, CD86, CD83, and HLA-DR expression (A) and PDL-1, PDL-2, ILT3, and ILT4 expression (B) by unstimulated, MF-primed, and MF/2.5 μM VitD3–primed DDCs and LCs is shown. Graphs show 1 representative experiment of at least 10 experiments. C, IL-12-p70, TNF-α, and IL-10 production by MF- and MF/VitD3-primed DDCs and LCs (n = 5). ∗P < .05. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 IL-10 is essential for the induction of IL-10–producing Treg cells by DDCs, whereas TGF-β is essential for the induction of Foxp3high T cells by LCs. A, Induction of IL-10–producing CD4+ T cells by MF/VitD3-primed DDCs in the absence and presence of anti–IL-10 or anti–TGF-β/SMAD3i. B, Induction of CD127−Foxp3+ T cells by MF/VitD3-primed LCs in the absence and presence of anti–TGF-β, SMAD3i, or anti–IL-10. C and D, Suppression of target cell proliferation by T cells stimulated by DDCs or LCs primed with MF/VitD3 in the presence of anti–IL-10 and SMAD3i, respectively. E and F, Induction of IL-10–producing T cells and CD127−Foxp3+ T cells by skin-derived DDCs and LCs after priming with MF/VitD3 in the presence of anti–IL-10 or anti–TGF-β/SMAD3i, respectively. Data show the mean ± SD of 5 (Fig 7, A and B), 3 (Fig 7, C), or 2 (Fig 7, D and E) independent experiments. ∗P < .05. DMSO, Dimethyl sulfoxide. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Phenotype of in vitro–generated LCs and DDCs
Phenotype of in vitro–generated LCs and DDCs. Representative results for E-cadherin and CD1A (A) and langerin (B) expression of in vitro–generated LCs and DDCs. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 T cells stimulated by DDCs or LCs primed with MF/VitD3 suppress proliferation of bystander T cells. Representative 5,6-carboxy fluorescein diacetate succinimidyl ester–stained pictures showing proliferation of bystander T cells (target cells) in the presence of T cells stimulated by in vitro–generated DDCs or LCs primed with MF and various VitD3 concentrations (n = 3). Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Effects of different VitD3 concentrations on maturation of DDCs and LCs. CD14, CD86, CD83, HLA-DR, and CD80 expression of unstimulated, MF-primed, and MF/VitD3-primed DDCs and LCs by using various VitD3 concentrations is shown. Graphs show 1 representative experiment of 3. iDC, Immature DC. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 LCs have a high constitutive TGF-β expression that is not enhanced by VitD3. Expression of active TGF-β1 by DDCs and LCs on stimulation with MF or MF/VitD3, as measured by means of capture ELISA, is shown. Data show the mean of 2 independent experiments. iDC, Immature DC. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 DDC-derived IL-10 is essential for the induction of IL-10–producing Treg cells by DDCs. Induction of IL-10–secreting cells by MF/VitD3-primed DDCs in the presence of anti–IL-10 measured by means of IL-10 secretion assay is shown (n = 1). Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 LC-derived TGF-β is essential for the induction of Foxp3+ T cells by LCs. Representative pictures show the induction of CD127−Foxp3+ T cells by MF/VitD3-primed LCs in the absence and presence of anti–TGF-β, SMAD3i, or anti–IL-10. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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