Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong Th17/Th1 T-cell responses Anja Hänsel,

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Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong Th17/Th1 T-cell responses Anja Hänsel, PhD, Claudia Günther, MD, Jens Ingwersen, MD, Josephine Starke, MD, Marc Schmitz, MD, Michael Bachmann, PhD, Michael Meurer, MD, Ernst Peter Rieber, MD, Knut Schäkel, MD Journal of Allergy and Clinical Immunology Volume 127, Issue 3, Pages 787-794.e9 (March 2011) DOI: 10.1016/j.jaci.2010.12.009 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Production of Th17 and Th1–inducing cytokines. SlanDCs, CD1c+ DCs, and monocytes isolated by magnetic cell sorting (precultured for 6 hours) were stimulated with LPS (100 ng/mL) or PGN (10 μg/mL) for 24 hours. The production of cytokines was determined by ELISA in cell-free supernatants. Data from 9 experiments are shown (means ± SEMs). ∗∗∗P ≤ .001, ∗∗P ≤ .01, ∗P ≤ .05, CD1c+ DCs and monocytes vs slanDCs (Student t test). CTRL, Control. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 SlanDCs program Th17/Th1 T cells. SlanDCs (filled symbols) or CD1c+ DCs (shaded symbols) (A and C) were cocultured (ratio, 1:10) with CD4+, CD45RA+ (A and B) or CD4+, CD45RA+, CD45RO- T cells (C and D). Cultures were harvested and restimulated on day 7 with ionomycin and PMA. After 24 hours, cytokines were quantified by ELISA in cell-free supernatants (A). For intracytoplasmatic cytokine staining (B and D), cells were restimulated for 6 hours, adding brefeldin A for the last 5 hours to inhibit cytokine secretion. LPS (100 ng/mL) and IFN-γ (100 ng/mL) were added to the primary DC/T–cell culture as indicated (B and D). Data of 4 individual donors are shown (A; means ± SEMs). One representative (B and D) or the mean of 6 individual experiments is given (C).∗∗∗P ≤ 0.001; ∗∗P ≤ 0.01; ∗P ≤ 0.05. ns, Not significant. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 SlanDCs in healthy skin and psoriasis. Immunohistochemical stainings (mAb DD2) of normal human skin (A) and lesional psoriasis (B and C) were performed to detect slanDCs. Box plots (C) show the result of multiple samples: plaque psoriasis (n = 10; 61 sections), psoriasis palmoplantaris (n = 5; 19 sections), and healthy skin (n = 14; 56 sections). The differences for healthy skin and psoriasis were significant (P = 5 × 10−11). slan, 6-Sulfo LacNAc. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 IL-23p19, TNF-α, and iNOS–expressing slanDCs in lesional psoriasis. Immunofluorescence staining was done on sections of healthy (A) and psoriatic skin (B). B, Images of single stainings and merged images. The punctured line denotes the dermal-epidermal junction. Panels on the right display an area at higher magnification. Similar results were obtained in at least 10 other skin samples studied. Original magnification ×200. slan, 6-Sulfo LacNAc. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Skin recruitment of slanDCs. A, Overview and details of immunohistochemical staining for slanDCs in psoriatic skin (mAb DD2). SlanDCs were found on the luminal (filled arrow) and abluminal side of the vessels. B, Expression of chemokine receptors on slanDCs, CD1c+ DCs, monocytes, and pDCs as determined by flow-cytometric analysis (open histogram, isotype control). Results are representative for at least 5 different donors. MFI, Mean fluorescent intensity. C, In vitro migration assays adding C5a (100 ng/mL), CX3CL1, or CXCL12 to the lower chamber and the cells to the upper part of a transwell insert (8-μm pore filter). Transmigrated slanDCs were quantified by flow cytometry. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Activation of slanDCs by self-RNA–LL37 complexes and R848. A, TNF-α production of slanDCs (filled circles) and CD1c+ DCs (shaded circles). Values of individual donors are shown. Freshly isolated slanDCs were cultured for 24 hours in the presence of LL37 (10 μg/mL), human RNA (4 μg/mL), or LL37 and RNA. To allow for complex building, LL37 and RNA were mixed for 30 minutes before DC stimulation. B, Production of cytokines of R848-stimulated and control PBMCs was determined by intracellular cytokine staining combined with electronic gating to identify respective DC subsets as described.11 Given are the mean fluorescence intensities (MFIs) and the SEMs obtained in 4 experiments. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Maturation–dependent IL-23, IL-12, IL-1ß, and IL-6 production of slanDCs. Either freshly isolated or 6 hours in vitro–matured slanDCs were stimulated as indicated to induce cytokine production. Given are the means ± SEMs of 6 donors studied. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Enhanced IFN-γ and IL-17 production of T cells stimulated by slanDCs Enhanced IFN-γ and IL-17 production of T cells stimulated by slanDCs. CSFE-labeled T cells were cocultured with slanDCs or CD1c+ DCs and evaluated on day 5 for their proliferation and their production of IFN-γ by intracytoplasmatic cytokine staining after 6 hours of culture in the presence of brefeldin A (A). B and C, Primary mixed leukocyte reactions with CD4+, CD45RA+ T cells stimulated by allogeneic slanDCs or CD1c+ DCs in the absence or in the presence of 100 ng LPS/mL were set up, and IFN-γ (B) and IL-17 (C) were quantified in cell-free culture supernatants harvested at different days of culture. The means and SEMs of 5 experiments are shown (B and C), and results of 1 representative experiment of 4 are shown (A). Tn, Naive T cells. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

TNF-α and IL-10 production of T cells programmed by slanDCs or CD1c+ DCs. The cytokine production of restimulated T-cell cultures initially stimulated by slanDCs and CD1c+ DCs was determined by ELISA (A) and intracellular cytokine staining (B). IL-2 (50 U/mL on day 4) was added as indicated. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Specificity of the anti–6-sulfo LacNAc mAb DD2 in psoriasis Specificity of the anti–6-sulfo LacNAc mAb DD2 in psoriasis. Three-color immunofluorescence staining was performed for indicated markers to identify DD2+ slanDCs, CD3+ T cells, CD20+ B cells, mast cell tryptase+ mast cells, CD1a+ dermal and epidermal DCs, and CD123+ pDCs. At least 5 patients with psoriasis vulgaris were analyzed for each marker. Original magnification ×200. slan, 6-Sulfo LacNAc. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Phenotype of IL-23p19–producing cells in lesional psoriatic skin Phenotype of IL-23p19–producing cells in lesional psoriatic skin. Three-color immunofluorescence staining was performed for indicated markers to identify IL-23p19–producing cells in psoriasis skin sections. At least 5 patients with psoriasis vulgaris were analyzed for each marker. Original magnification ×200. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Frequency of slanDCs, CD1c+ DCs, pDCs, and CD14+ monocytes in blood of patients with psoriasis and healthy donors. The frequency of different cell types among PBMCs as analyzed by flow cytometry. CD1c+ DCs were defined as lineage marker negative (lin–; CD3, CD19, CD20, CD56, CD14, CD16), HLA-DR+, CD123–, CD11c+. pDCs were defined as lin–, HLA-DR+, CD123+, CD11c–. SlanDCs were identified by staining for the 6-sulfo LacNAc antigen. Monocytes were identified as CD14+ cells. Journal of Allergy and Clinical Immunology 2011 127, 787-794.e9DOI: (10.1016/j.jaci.2010.12.009) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions