The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune.

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The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune responses in the setting of allergic asthma Caroline Übel, PhD, Nina Sopel, MSc, Anna Graser, BS, Kai Hildner, MD, Cornelia Reinhardt, MD, Theodor Zimmermann, MD, Ralf Joachim Rieker, MD, Anja Maier, MSc, Markus F. Neurath, MD, Kenneth M. Murphy, MD, Susetta Finotto, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 1, Pages 198-206.e9 (January 2014) DOI: 10.1016/j.jaci.2013.09.049 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased BATF mRNA expression in the setting of allergic asthma. A, BATF mRNA expression in PBMCs of children with asthma not treated with steroids (AnS), children with asthma treated with steroids during reacutization (AS), and control children (CC; CC, n = 9; AnS, n = 4; and AS, n = 6). B and C, AHR (Buxco [Fig 1, B] and SCIREQ [Fig 1, C], respectively; n = 3-7 per group). RL, Airway resistance; Rrs, respiratory system resistance. D-G, BAL differential cell counts (n = 3-9 per group). H and I, Hematoxylin and eosin and periodic acid–Schiff (PAS) staining of lung sections (n = 3-9 per group). *P < .05, **P < .01, and ***P < .001, ANOVA (Fig 1, B and C) or Student 2-tailed t test (Fig 1, A and D-I). WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Batf−/− mice have a defect in OVA-specific IgE and IL-3 levels and mast cell development. A-E, Lung inflammation and BALF cytokine or serum immunoglobulin levels (n = 3 per group). F and G, Serum IgE and IgG2a levels (n = 3-6 per group). H, Lung mast cells (n = 4 per group). I and J, ELISA for IL-3 (n = 3-4 per group). K, Flow cytometry (left) and cytospin (right) of d25 BMMCs (n = 3 per group). L, BMMC histamine (n = 5 per group). M, BMMC apoptosis (Annexin V+ propidium iodide–negative cells). *P < .05, **P < .01, and ***P < .001, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 BATF controls TH17 and TH2 cells in the setting of asthma. A and B, Supernatants were analyzed for IL-17A (Fig 3, A) and IL-21 (Fig 3, B) production. C, Rorc mRNA expression. D, Lung IL-10 levels (n = 3-6 per group). E, BALF IL-9 levels (n = 5). F, Lung CD4+ cytokine secretion. G, Gata3 mRNA expression (n = 3-6 per group). H, Lung tissue pSTAT5 and STAT5 levels in asthmatic mice (n = 3-4 per group). I, Lung IL-2 levels (n = 3-4 per group). J, Lung activated T cells (n = 8-10 per group). K, Lung Treg cells (n = 4 per group). *P < .05, **P < .01, and ***P < .001, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Increased IFN-γ production in CD4+ and CD8+ T cells in the airways of Batf−/− mice. A, BALF IFN-γ levels. B-D, Cells were stained for IFN-γ and T-cell surface markers (n = 3-4 per group). *P < .05 and **P < .01, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Local treatment with anti–IFN-γ antibody in Batf−/− mice and wild-type (WT) littermates. A, Serum IgE. B, Hematoxylin and eosin–stained lung sections (n = 4 per group). C-E, Lung mast cells (Fig 5, C), invasive AHR (Fig 5, D), and Lung Treg cells (Fig 5, E; n = 3 per group). *P < .05, **P < .01, and ***P < .001, ANOVA (Fig 5, D) or Student 2-tailed t test (Fig 5, A-C and E). Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Measurement of noninvasive AHR and characterization of lung cell populations and cytokine levels in BALF. A, Schematic representation of the experimental asthma protocol used in this study with 2 intraperitoneal injections of OVA/alum on days 0 and 7, followed by intranasal challenge with OVA on days 18, 19, and 20. B, AHR was measured by using noninvasive plethysmography in naive mice and after OVA treatment (n = 5-7 per group). C-E, Total lung cells from naive wild-type and Batf−/− mice were analyzed by means of flow cytometry for surface markers of macrophages (Fig E1, C), dendritic cells (Fig E1, D), and CD3+ T cells (Fig E1, E). F-H, GM-CSF (Fig E1, F), TNF-α (Fig E1, G), and IL-5 (Fig E1, H) secretion from untreated and OVA-sensitized and OVA-challenged mice was measured with an ELISA (n = 3-6 per group). Data are presented as mean values ± SEMs. **P ≤ .01 and *** P ≤ .001, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 BALF histamine levels and IL-3 dependency of BMMCs. A, Total histamine levels were determined with ELISA in BALF of OVA-treated wild-type and Batf−/− mice. B, Dot plots from an apoptosis assay after cytokine deprivation of BMMCs (n = at least 3 readouts per group). Data are mean values ± SEMs. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Cytokine levels of OVA-restimulated total lung cells and decreased numbers of activated T cells and Treg cells in lungs of Batf−/− mice. A-D, Total lung cells from control or OVA-treated mice were restimulated with OVA in vitro, and levels of cytokines (IL-4, IL-5, IL-13, and IL-10) were measured in the supernatants (n = 3 per group). E and F, CD4+CD25+ activated T-cell numbers (Fig E3, E) and CD4+CD25+FoxP3+ Treg cell numbers (Fig E3, F) were determined by using cytometry, and the number of gated lymphocytes was analyzed (n = 4-10 per group). Data are presented as mean values ± SEMs. *P ≤ .05, **P ≤ .01, and ***P ≤ .001, Student 2-tailed t test. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Determination of IFN-γ+ lung cells in untreated and OVA-treated mice by using flow cytometry. A-C, Percentage of IFN-γ+ cells in the natural killer cell, dendritic cell, and macrophage compartments in naive wild-type and Batf−/− mice. D-I, IFN-γ+ cell numbers calculated with the number of gated cells (n = 3-6 per group). Data are mean values ± SEMs. *P ≤ .05 and **P ≤ .01, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Effects of anti–IFN-γ antibody treatment on cytokine secretion and mast cell numbers. A, Schematic representation of the asthma protocol used in this study. On days 18 and 20, mice received 100 μg of either control IgG or anti–IFN-γ antibodies per day. B, BALF cells were stained with May-Grünwald-Giemsa and analyzed by using light microscopy. C and D, Analysis of IL-4 and IL-5 levels from total lung cells and in BALF of IgG or anti–IFN-γ–treated wild-type or Batf−/− mice in a murine model of experimental asthma. E, IL-3 secretion from total lung cells. F, Lung mast cells were measured with flow cytometry, and cell numbers of gated cells were determined (n = 4-5 per group). Data are mean values ± SEMs. *P ≤ .05, **P ≤ .01, and ***P ≤ .001, Student 2-tailed t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Cytokine levels and Treg cell numbers after anti–IFN-γ antibody treatment. A-D, IL-17A, IL-10, IL-9, and IL-13 levels were measured by means of ELISA in BALF (Fig E6, A) or total lung cell supernatants (Fig E6, B-D) from mice treated with anti–IFN-γ antibodies or control IgG in a murine model of asthma. E, Lung Treg cell numbers were determined with flow cytometry, and the number of gated cells was taken into account (n = 4-5 per group) Data are mean values ± SEMs. *P ≤ .05 and **P ≤ .01, Student 2-tailed t test. Journal of Allergy and Clinical Immunology 2014 133, 198-206.e9DOI: (10.1016/j.jaci.2013.09.049) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions