Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4–dependent dermal dendritic cells Julie Deckers, MSc, Dorine.

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Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4–dependent dermal dendritic cells Julie Deckers, MSc, Dorine Sichien, MSc, Maud Plantinga, PhD, Justine Van Moorleghem, BSc, Manon Vanheerswynghels, BSc, Esther Hoste, PhD, Bernard Malissen, PhD, David Dombrowicz, PhD, Martin Guilliams, PhD, Karolien De Bosscher, PhD, Bart N. Lambrecht, MD, PhD, Hamida Hammad, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 5, Pages 1364-1377.e2 (November 2017) DOI: 10.1016/j.jaci.2016.12.970 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HDM sensitization through the skin does not depend on barrier disruption or proteolytic activity of the allergen. A, Protocol of allergic airway inflammation induced by epicutaneous sensitization to HDM. B, Differential cell counts in BAL fluid. C, Serum levels of HDM-specific IgE. D, Cytokine production by MLN cells. E, Siglec-F (left) and Muc5ac (right) confocal staining in lungs. 4′-6-Diamidino-2-phenylindole dihydrochloride (DAPI) was used for nucleus counterstaining. F, TEWL after overnight tape occlusion (tape ON) or acute tape stripping. G, Frequencies of neutrophils and DCs in SCLNs after overnight tape occlusion. H, Differential cell counts in BAL fluids after epicutaneous HDM application in the absence of tape occlusion. I, Effect of the enzymatic activity of HDM on cell counts in BAL fluid. J, Cytokine production by MLN cells. Data represent means ± SEs (n = 5-10 mice per group). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Sensitization through the skin occurs only in the skin-draining LNs, and this is Der p 1 specific. A, Proliferation (CFSE dilution) and activation (CD44 expression) of 1-DER T cells in draining (SCLN) and nondraining LNs 4 days after epicutaneous HDM application. B and C, Percentage of cells in division (Fig 2, B) and CD44+ cells in draining SCLNs and nondraining LNs (ILN; Fig 2, C) 4 or 7 days after epicutaneous application of HDM or PBS. D, Cytokine production by SCLN cells. E-G, The same protocol as in Fig 2, A-D, was repeated by using Rag−/− 1-DER CD4+ T cells. Data are representative of 4 independent experiments and shown as means ± SEs (n = 3-6). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Gating strategy of DC subsets in the skin and skin-draining LNs. A, Gating strategy of DC subsets in the skin of naive C57Bl/6 mice. B, Gating strategy of DC subsets in skin-draining LNs (SCLN) 24 hours after epicutaneous treatment with HDM. C, Expression of different markers in skin DC subsets. D, Expression of different markers in migratory DC subsets from SCLNs. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Epicutaneous (e.c.) application of HDM induces migration of DCs to the draining LNs. A, Kinetics of DC migration in SCLNs after epicutaneous application of HDM. B and C, Uptake of fluorescent HDM by skin CD45+ cells (Fig 4, B) and number of total skin macrophages (MFs) and DC subsets (Fig 4, C) 4 hours after epicutaneous PBS (white bars) and HDM (gray bars) application. D, Number of HDM-AF647+ cells in the skin 4 hours after epicutaneous application of HDM-AF647. E and F, Uptake of fluorescent HDM by CD45+ SCLN cells (Fig 4, E) and number of total DC subsets (Fig 4, F) in the SCLNs 48 hours after epicutaneous application of PBS or HDM-AF647. G, Number of HDM-AF647+ cells in the SCLNs 2 days after epicutaneous application of PBS or HDM-AF647. Data are representative of at least 2 independent experiments and shown as means ± SEs (n = 6). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Allergic airway inflammation induced by skin sensitization depends on cDC2s. A, D, and G, Number of migratory DC subsets in the SCLNs of Flt3−/−, Lang-DTR, and Irf4fl/fl Cd11c-Cre mice, respectively, in steady-state conditions. B, E, and H, Differential cell counts in BAL fluids. C, F, and I, Cytokine production of MLN cells. Data are representative of at least 2 independent experiments and shown as means ± SEs (n = 5-6). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IRF4-dependent cDC2s are sufficient to induce allergic airway inflammation to HDM. A, Experimental setup. B, Proliferation and CD44 expression of 1-DER CD4+ T cells cocultured ex vivo with sorted HDM+ DC subsets. C and D, Differential cell counts in BAL fluid (Fig 6, C) and cytokine production of MLN cells (Fig 6, D) from mice injected intradermally with HDM+ DC subsets. In Fig 6, B, data are representative of at least 4 independent experiments. In Fig 6, C and D, data from 2 independent experiments have been pooled and shown as means ± SEs (n = 4-12). *P < .05. e.c., Epicutaneous; i.d., intradermal, i.n., intranasal. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Sensitization through the skin requires CCR7-dependent active transport of HDM to the draining LNs. CFSE-labeled WT 1-DER CD4+ T cells were injected intravenously in C57Bl/6 mice applied with HDM or PBS on the ear skin. A, Proliferation of injected 1-DER T cells in draining (ipsilateral SCLN) and nondraining (contralateral ILN) LNs 4 days after epicutaneous application of HDM extract or PBS control. B, Percentage of cells in division. Data are representative of 2 independent experiments and shown as means ± SEs (n = 6-7). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 LCs are not involved in TH2 sensitization to epicutaneously applied HDM. Lang-DTR mice and their WT counterparts were injected intraperitoneally with 500 ng of diphtheria toxin (DT) or PBS on day 0. On day 7, mice were sensitized with HDM or PBS epicutaneously and challenged with HDM intranasally on days 14 to 18. Differential cell counts in BAL fluid (A) and cytokine production of MLN cells (B) restimulated with HDM for 3 days ex vivo. Data are shown as mean ± SEs (n = 5-6). *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1364-1377.e2DOI: (10.1016/j.jaci.2016.12.970) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions