Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost,

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Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost, PhD, Antonio Cappuccio, PhD, Jean-Christophe Bichet, MD, Olfa Chouchane-Mlik, MD, Marie-Hélène Donnadieu, MSc, Emmanuel Barillot, PhD, Philippe Hupé, PhD, Katerina Chlichlia, PhD, Eleni I. Efremidou, MD, PhD, Selim Aractingi, MD, Olivier Bayrou, MD, Vassili Soumelis, MD, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 233-240.e5 (July 2012) DOI: 10.1016/j.jaci.2012.04.038 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-17A and IL-17F specifically inhibit TSLP production induced by TNF-α and IL-4 in human skin explants. A-F, TSLP (Fig 1, A-C) and IL-8 (Fig 1, D-F) quantification by means of protein ELISA. Each symbol represents an independent experiment (n = 4). Horizontal bars indicate the median. Statistical significance is retained for pairwise comparison between culture condition groups. ∗P < .05 and false discovery rate > 0.1. #P < .05 and false discovery rate < 0.1. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-17A inhibits established TSLP production by human atopic dermatitis (AD) skin explants. A, Frozen sections of cultured AD skins stained by means of immunohistology for TSLP. B-D, Percentages of staining are shown for all patients (Fig 2, B) or divided into patients with moderate (Fig 2, C) and severe (Fig 2, D) AD. Each symbol represents a different donor (n = 7). Horizontal bars indicate the median. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TH17-polarizing cytokines enhance the maturation and production of CCL22 and IL-8 by TSLP-DCs. A, CD40, CD80, and CD86 expression assessed by means of flow cytometry (mean fluorescence intensity [MFI] level, mean ± SEM, n = 3). B, CCL17, CCL22, and IL-8 quantification by means of ELISA or cytometric bead assay in 48-hour DC supernatants (mean ± SEM, n = 5). Statistical significance is indicated for pairwise comparison of culture condition groups. ∗P < .05; ∗∗P < 0.01; #P < 0.05 and false discovery rate < 0.1. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TH17-polarizing cytokines inhibit the TSLP-DC–induced inflammatory TH2 differentiation. A, The TH profile was assessed based on cytokine production (median, n = 11, pairwise comparison). #P < .05 and false discovery rate < 0.1. B, Star-shaped figure of TH profile. The length of a spoke is proportional to the average of a cytokine concentration of that profile. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Dominance of the TH17-polarizing cytokines over TSLP-DC–induced inflammatory TH2 differentiation. A, MANOVA of TH profiles (n = 11). Points in the plane represent the average of the first (MC1) and second (MC2) coordinates of each TH subset. The ellipses around the points represent the SD. B, Dendrogram using the Mahalanobis distance between multivariate group means. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 IL-17A and IL-17F dose-dependent inhibition of TSLP in human skin explants. A-D, TSLP (Fig E1, A and B) and IL-8 (Fig E1, C and D) quantification by means of protein ELISA. Each symbol represents a different donor assayed in an independent experiment (n = 3). Horizontal bars indicate the median. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 IL-17A inhibits ongoing TSLP production by human skin explants. TSLP quantification by means of protein ELISA is shown. Each symbol represents a different donor assayed in an independent experiment (n = 7). Horizontal bars indicate the median. ∗P < .05; ∗∗P < .01. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IL-17A does not affect the TSLP-induced DC maturation or the TSLP-DC–induced inflammatory TH2 response. A and B, DC activation marker expression from 1 representative of 3 independent experiments. The mean fluorescence intensity (MFI) expression is noted in each corresponding plot (Fig E3, A) and in a histogram (Fig E3, B; MFI ± SEM). C, Cytokine production measured by means of cytometric bead assay (n = 4). Horizontal bars indicate the median. ns, P > .05. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Effect of TH17-polarizing cytokines on TSLP-DC–induced inflammatory TH2 differentiation. Twenty-four-hour TSLP-activated DCs were cocultured for 6 days with naive T cells with or without different combinations of IL-1β, IL-6, TGF-β, and IL-23. IL-4 (A), IL-5 (B), and IL-13 (C) were quantified by means of cytometric bead assay. Each symbol represents an independent experiment (n = 4). Horizontal bars indicate the median. Each condition is compared with the TSLP-DC-Med condition. ∗P < .05; #P < .05 and false discovery rate < 0.1. Journal of Allergy and Clinical Immunology 2012 130, 233-240.e5DOI: (10.1016/j.jaci.2012.04.038) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions