Increased expression of nuclear factor of activated T cells 1 drives IL-9–mediated allergic asthma Sonja Koch, PhD, Anna Graser, PhD, Hooman Mirzakhani,

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Increased expression of nuclear factor of activated T cells 1 drives IL-9–mediated allergic asthma Sonja Koch, PhD, Anna Graser, PhD, Hooman Mirzakhani, MD, PhD, MMSc, Theodor Zimmermann, MD, Volker O. Melichar, MD, Marco Wölfel, MD, Damien C. Croteau-Chonka, PhD, Benjamin A. Raby, MD, MPH, Scott T. Weiss, MD, MS, Susetta Finotto, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 6, Pages 1898-1902.e7 (June 2016) DOI: 10.1016/j.jaci.2015.11.047 Copyright © 2016 The Authors Terms and Conditions

Fig 1 Increased expression of NFATc1 in atopic children with asthma. A, NFATc1 gene transcript isoforms or variants. B, Schematic representation of the PreDicta analysis. C, NFATc1 mRNA expression was analyzed by using quantitative real-time PCR in PBMCs (n = 12-17 children per group). D, Children shown in Fig 1, C, were further subdivided into healthy children with negative skin test results (n = 5) and asthmatic children with positive skin test results (n = 13). E, IFNG mRNA expression analyzed by using quantitative real-time PCR in RNA isolated from whole blood (n = 6 and 15 children per group). F, Schema of the subjects and their obtained gene expression profiles from Asthma BRIDGE Cohort. Statistical significance in this figure was evaluated with the Student t test. *P ≤ .05 and **P ≤ .01. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2016 137, 1898-1902.e7DOI: (10.1016/j.jaci.2015.11.047) Copyright © 2016 The Authors Terms and Conditions

Fig 2 Increased mRNA expression and IL-9 production in asthmatic patients with a positive skin test result. A, IRF4 mRNA expression analyzed by using quantitative real-time PCR in RNA isolated from whole blood (n = 13-14 children per group). B and C, Further subdivision of children shown in Fig 2, A, into healthy subjects with negative skin test results (n = 6, PreDicta, Fig 2, B; n = 104, Asthma BRIDGE, Fig 2, C) and asthmatic patients with positive skin test results (n = 8, PreDicta, Fig 2, B; n = 144, Asthma BRIDGE, Fig 2, C). D and E, PBMCs from the PreDicta children were cultured with PHA for 48 hours, and afterward, ELISA was performed for IL-9 production on cell supernatants (Fig 2, D: n = 19 healthy children and n = 20 asthmatic children; Fig 2, E: n = 8 healthy children with negative skin test results and n = 15 asthmatic children with positive skin test results). The Student t test was used to evaluate statistical significance. *P ≤ .05 and **P ≤ .01. Data are presented as means ± SEs. Journal of Allergy and Clinical Immunology 2016 137, 1898-1902.e7DOI: (10.1016/j.jaci.2015.11.047) Copyright © 2016 The Authors Terms and Conditions

Fig E1 Decreased IL-9 production in NFATc1fl/flxCD4Cre mice after allergen sensitization and challenge. A, Experimental design of the OVA-induced asthma model. B, IL-9 protein concentrations were measured in supernatants of purified lung CD4+ T cells from allergen-treated mice and cultured for 24 hours with α-CD3 and α-CD28 antibodies (n = 7-11 mice per group). C, Irf4 mRNA expression measured by using quantitative real-time PCR in isolated lung CD4+ T cells (n = 8-13 mice per group). D, Correlation between Nfatc1/A mRNA expression in lung CD4+ T cells and OVA-specific IgE levels in serum of Nfatc1fl/fl OVA-treated mice (n = 6). E, Correlation between Irf4 mRNA expression in lung CD4+ T cells and OVA-specific IgE in serum of Nfatc1fl/fl OVA mice (n = 6). The Student t test was used to evaluate statistical significance. *P ≤ .05. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2016 137, 1898-1902.e7DOI: (10.1016/j.jaci.2015.11.047) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Decreased mast cell numbers and activation in NFATc1fl/flxCD4Cre mice. A, Mast cell numbers (c-kit+FcεRI+CD123+ cells) were analyzed by using flow cytometry in the lungs of NFATc1fl/fl control mice and NFATc1fl/flx CD4Cre mice (n = 4-11 mice per group). B, IgE serum levels were measured with ELISA (n = 12-19 mice per group). C, Experimental design for bone marrow–derived mast cell (BMMC) differentiation (upper panel) and histamine release (lower panel). Histamine release was measured by means of ELISA (lower panel; n = 4 mice per group). Mast cells differentiated from Nfatc1fl/flxCD4Cre mice received serum from OVA-sensitized and challenged Nfatc1fl/flxCD4Cre mice, whereas mast cells from Nfatc1fl/fl mice received serum from OVA-sensitized and challenged Nfatc1fl/fl mice. Statistical significances in this figure were evaluated with the Student t test. *P ≤ .05, **P ≤ .01, and ***P ≤ .001. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2016 137, 1898-1902.e7DOI: (10.1016/j.jaci.2015.11.047) Copyright © 2016 The Authors Terms and Conditions

Fig E3 Mast cell differentiation. A, Flow cytometric analysis of bone marrow–derived mast cell differentiation, as described in the Methods section in this article's Online Repository. FACS analysis for FcεRI+c-kit+ cells was performed every week to monitor the differentiation status of the cultured cells. B, Corresponding dot plots from the first and fourth weeks of mast cell differentiation are shown. Journal of Allergy and Clinical Immunology 2016 137, 1898-1902.e7DOI: (10.1016/j.jaci.2015.11.047) Copyright © 2016 The Authors Terms and Conditions