Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy Maryam Hussain, MSc, Loïc Borcard,

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Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy Maryam Hussain, MSc, Loïc Borcard, MSc, Kevin P. Walsh, PhD, Maria Pena Rodriguez, BSc, Christoph Mueller, PhD, Brian S. Kim, MD, Masato Kubo, PhD, David Artis, PhD, Mario Noti, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 223-234.e5 (January 2018) DOI: 10.1016/j.jaci.2017.02.035 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 223-234 Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Epicutaneous food antigen sensitization is associated with infiltration of IL-4–competent innate immune cells. A, Kinetics of IL-4eGFP+ skin-infiltrating cells in response to topical MC903 plus OVA treatment. B, Frequencies of Siglec-F+, c-Kit+, and double-negative CD3−IL-4 eGFP+ cells in the skin. C, Total numbers of CD3−IL-4eGFP+Siglec-F+c-Kit−, c-Kit+Siglec-F−, and double-negative cells in the skin. D, Frequencies of basophils (CD49b+, IgE+) in the Siglec-F−c-Kit− cell fraction in Fig 1, C. Basophils were gated as live, singlet, CD45+, Lin−, c-Kit−, and Siglec-F− cells coexpressing CD49b and IgE. Data are representative of 3 independent experiments with 3 to 5 mice per group. Error bars indicate means ± SDs. **P < .01 and ***P < .005. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Absence of eosinophils does not alter disease pathogenesis of IgE-mediated food allergy. A, Experimental protocol. i.g., Intragastric. B, Ear swelling. C, Hematoxylin and eosin staining from the skin. Scale bar = 100 μm. D, Numbers of skin-infiltrating basophils. E, Allergy score. F, OVA-specific serum IgE levels. G, Serum mouse mast cell protease 1 (MMCP-1) levels. H, Representative fluorescence-activated cell sorting plots of mast cells in the small intestinal lamina propria. Mast cells were gated as live, CD45+, lin− (CD3−, CD5−, CD19−, CD11c−, and NK1.1−), and Siglec-F– cells coexpressing c-Kit and IgE. I, Quantification of mast cell frequencies in the small intestinal lamina propria. J, Chloroacetate esterase staining of mast cells from the jejunum. Scale bar = 100 μm. K, Quantification of chloroacetate esterase–positive mast cells. Data are representative of 3 independent experiments with 4 to 5 mice per group. Solid bars represent WT animals, and open bars represent ΔdblGATA mice. Error bars indicate means ± SDs. ND, No disease; ns, not significant. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Basophil-derived IL-4 production promotes optimal TH2 polarization in vitro. Bone marrow from WT or IL-4−/− mice was cultured for 5 days with recombinant TSLP, and sort-purified basophils were cocultured with DCs alone or with DCs and OT-II T cells in the presence of OVA peptide for 4 days. A, Frequencies of IL-4+ and IFN-γ+ CD4+ OT-II T cells cocultured with DCs alone. B and C, Frequencies of IL-4+ and IFN-γ+ CD4+ OT-II T cells cocultured with DCs and increasing numbers of IL-4–sufficient (Fig 3, B) or IL-4–deficient (Fig 3, C) basophils are shown. Data are representative of 1 of 3 experiments. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Basophils and DCs undergo reciprocal interactions to promote TH2 differentiation in vitro. A, Frequencies of OVA peptide–stimulated IL-4+ and IFN-γ+ CD4+ OT-II T cells cocultured with DCs alone. B, Frequencies of OVA peptide–stimulated IL-4+ and IFN-γ+ CD4+ OT-II T cells cocultured with DCs together or separated by transwells from basophils alone or basophils and DCs. C, Surface expression of OX40L (mean fluorescence intensity) on DCs stimulated with LPS or papain or DCs coincubated together or separated from basophils by using a transwell. Gray histograms, DCs incubated with medium alone. Bold black lines, Treated DCs. D, IL-4 protein levels in supernatants of DC and basophil cocultures. Data shown are representative of 1 of 3 experiments. TW, Transwell. **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Basophil-intrinsic IL-4 production regulates epicutaneous antigen sensitization. A, Hematoxylin and eosin staining from the skin. B, Ear swelling. C, Representative fluorescence-activated cell sorting plots of basophils in the skin. Basophils were gated as live, CD45+, lin− (CD3−, CD5−, CD19−, CD11c−, and NK1.1−), and c-Kit− cells coexpressing CD49b and IgE. D, Quantification of basophil frequencies in the skin. E, Mean fluorescence intensity of basophil-bound IgE. F, IL-5 and IL-13 production from restimulated skin-draining lymph nodes. Data are representative of 3 independent experiments with 4 to 6 mice per group. Solid bars represent WT animals, and open bars represent Il4-3′UTR mice. Error bars indicate means ± SDs. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Basophil-intrinsic IL-4 production promotes the development of IgE-mediated food allergy. A, Allergy score. B, OVA-specific serum IgE levels. C, Serum mouse mast cell protease 1 (MMCP-1) levels. D, Serum TSLP levels. E, Representative fluorescence-activated cell sorting plots of mast cells in the small intestinal lamina propria. Mast cells were gated as live, CD45+, and lin− (CD3−, CD5−, CD19−, CD11c−, and NK1.1−) cells coexpressing c-Kit and IgE. F, Quantification of mast cell frequencies in the small intestinal lamina propria. G, mRNA expression levels of Mmcp1 from the jejunum. H, Chloroacetate esterase staining of mast cells from the jejunum. I, Quantification of chloroacetate esterase–positive mast cells. Data are representative of 3 independent experiments with 4 to 6 mice per group. Solid bars represent WT animals, and open bars represent Il4-3′UTR mice. Error bars indicate means ± SDs. **P < .01 and ***P < .005. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 IL-4 is critical for the pathogenesis of IgE-mediated food allergy. A, Allergy score. B, OVA-specific serum IgE levels. C, Mast cell frequencies in the small intestine, as assessed by using flow cytometry. D, Mcpt1 expression levels in the small intestinal jejunum. Data are representative of 3 independent experiments with 3 to 4 mice per group. Error bars indicate means ± SDs. ND, No disease. ***P < .005. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 T-cell proliferation assay with DCs or TSLP-elicited basophils. Proliferation of OT-II T cells stimulated with OVA in the presence of DCs or TSLP-elicited basophils, as assessed by using carboxyfluorescein succinimidyl ester (CFSE) dilution. Data are representative of 1 of 3 experiments. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 DC surface expression of CD80 and CD40 in response to LPS, papain, or coincubation with TSLP-elicited basophils. Bone marrow–derived DCs (2 × 104 cells) were stimulated with LPS (100 ng/mL), papain (25 μg/mL), or coincubated with in vitro TSLP-elicited basophils (2 × 104 cells) for 24 hours. DC surface marker expression was then determined by means of flow cytometry for CD80 (A) and CD40 (B). Gray histograms represent DCs that were incubated with medium alone. Bold black lines represent treated DCs. Numbers indicate mean fluorescence intensity. Data shown are representative of 1 of 3 experiments. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Basophil depletion after epicutaneous food allergen sensitization does not result in complete ablation of mast cells in the small intestinal lamina propria. A, Experimental protocol. Basophils were depleted in Baso-DTR mice after epicutaneous food allergen sensitization by means of intraperitoneal injection of diphtheria toxin (DT) on days 15, 16, and 17. As a control, Baso-DTR mice were injected with PBS. B, Frequencies of basophils in the spleens of control-treated (no DT treatment) or DT-treated Baso-DTR mice. Basophils were gated as live, CD45+, lin− (CD3–, CD5–, CD19–, CD11c–, Siglec-F–, and NK1.1–), c-Kit– cells co-expressing IgE and CD49b. C, Mast cell frequencies in the small intestinal lamina propria of Baso-DTR mice treated with PBS (no DT treatment) or DT on days 15, 16, and 17. Mast cells were gated as live, CD45+, and lin− (CD3–, CD5–, CD19–, CD11c–, Siglec-F–, and NK1.1–) cells coexpressing c-Kit and IgE. Data are representative for 3 (Baso-DTR no DT treatment) and 4 mice (Baso-DTR + DT treatment). Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Depletion of CD4 T cells during the course of epicutaneous food allergen sensitization protects mice from IgE-mediated food allergy. A, Experimental protocol. B, CD4 T-cell frequencies in skin-draining lymph nodes. C, IgE serum levels. D, Allergy score. Data are representative of 2 independent experiments with 3 to 4 mice per group. Error bars indicate means ± SDs. **P < .01 and ***P < .005. Journal of Allergy and Clinical Immunology 2018 141, 223-234.e5DOI: (10.1016/j.jaci.2017.02.035) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions