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

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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 1532-1540.e7 (June 2011) DOI: 10.1016/j.jaci.2011.01.068 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2011 127, 1532-1540.e7DOI: (10.1016/j.jaci.2011.01.068) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions