Repressor of GATA regulates TH2-driven allergic airway inflammation and airway hyperresponsiveness Kiyoshi Hirahara, MD, Masakatsu Yamashita, PhD, Chiaki.

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Repressor of GATA regulates TH2-driven allergic airway inflammation and airway hyperresponsiveness Kiyoshi Hirahara, MD, Masakatsu Yamashita, PhD, Chiaki Iwamura, PhD, Kenta Shinoda, MS, Akihiro Hasegawa, PhD, Hirohisa Yoshizawa, MD, Haruhiko Koseki, MD, Fumitake Gejyo, MD, Toshinori Nakayama, MD Journal of Allergy and Clinical Immunology Volume 122, Issue 3, Pages 512-520.e11 (September 2008) DOI: 10.1016/j.jaci.2008.06.004 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased OVA-induced airway inflammation and AHR in ROG−/− mice. A, ROG+/+ and ROG−/− mice were sensitized with OVA and underwent inhalation with OVA. Infiltrated leukocytes in BAL fluid were assessed. The absolute cell number of eosinophils (Eos.), neutrophils (Neut.), lymphocytes (Lym.), and macrophages (Mac.) in the BAL fluid are shown with SDs. Seven to 8 mice per group were used. Three independent experiments were performed, and similar results were obtained. ∗P < .01, Student t test. B, Semiquantitative analysis of peribronchiolar leukocyte and eosinophil infiltration in the lung. ∗P < .01, Student t test. C, Hypermucus production was detected in ROG−/− mice. D, AHR was assessed as airway resistance (RL). Mean values (5 mice per group) are shown with SDs. ∗P < .01 and ∗∗P < .05, Kruskal-Wallis test. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Increased TH2 cytokine production in the airways of ROG−/− mice. A, The ability to differentiate into TH1/TH2 cells from ROG−/− x DO11.10 Tg mice was assessed. The results are representative of 5 experiments. B, mRNA levels of IL-4, IL-5, IL-13, eotaxin 2, RANTES, and TNF-α in BAL fluid cells were determined by using quantitative RT-PCR. ∗P < .01, Student t test. C, The amount of IL-5 and IL-13 in the BAL fluid was determined by means of ELISA. The mean values with SDs (3-5 mice per group) are shown. ∗P < .01 and ∗∗P < .05, Student t test. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Inhibition of OVA-induced airway inflammation and AHR in ROG Tg mice. A, Decreased infiltration of eosinophils in BAL fluid in asthmatic ROG Tg mice. Five mice per group were used. Two independent experiments were performed, and similar results were obtained. ∗P < .01 and ∗∗P < .05, Student t test. B, Semiquantitative analysis of peribronchiolar leukocyte infiltrates from H&E-stained (upper panel) and LUNA-stained (lower panel) samples. ∗P < .01, Student t test. C, Reduced mucus production in ROG Tg mice sensitized and challenged with OVA. D, AHR was assessed in an invasive assay system. Mean values (6 mice per group) are shown with SDs. ∗P < .01, Kruskal-Wallis test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Decreased TH2 cell differentiation and TH2 cytokine production in the airways of ROG Tg mice. A, The ability to differentiate into TH1/TH2 cells in vitro in ROG Tg x OT-II transgenic mice was assessed. The results are representative of 5 experiments. B, mRNA levels of IL-4, IL-5, IL-13, eotaxin 2, RANTES, and TNF-α in BAL fluid cells of wild-type and ROG Tg mice were determined by means of quantitative RT-PCR. ∗P < .01 and ∗∗P <.05, Student t test. C, The amount of IL-5 and IL-13 in the BAL fluid was determined by means of ELISA. The mean values with SDs (4 mice per group) are shown. ∗P < .01 and ∗∗P < .05, Student t test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Decreased airway inflammation in mice after adoptive transfer of ROG-overexpressing T cells. A, IFN-γ/IL-4 profiles of the transferred in vitro generated TH2 cells. B, Decreased infiltration of eosinophils in BAL fluid in mice receiving ROG-overexpressing T cells. Five mice per group were used. Two independent experiments were performed, and similar results were obtained. ∗P < .01, Student t test. C, mRNA levels of IL-4, IL-5, IL-13, eotaxin 2, RANTES, and TNF-α in the BAL fluid cells from adoptive transfer mice were determined by using quantitative RT-PCR. ∗P < .01, Student t test. D, One day after the last OVA inhalation, AHR was assessed, and results are presented as airway resistance (RL). Mean values (5-6 mice per group) are shown with SDs. ∗P < .01, Kruskal-Wallis test. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Modulation of airway inflammation by adoptive transfer of ROG−/− and ROG Tg T cells. A, Donor mice (ROG−/− and ROG Tg mice on a C57Bl/6 background) and recipient mice (C57BL/6) were sensitized with OVA. Splenic CD3 T cells were prepared from donor mice and transferred into recipient mice. Infiltrated leukocytes in BAL fluid are shown. Five mice per group were used. ∗P < .01 and ∗∗P < .05 between groups, Student t test. B, Semiquantitative analysis of peribronchiolar leukocyte infiltration (H&E stain), peribronchiolar eosinophil infiltration (LUNA stain), and the abundance of PAS-positive mucus containing cells (PAS stain). ∗P < .01 and ∗∗P < .05 between groups, Student t test. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Phenotypic characterization of thymocytes and peripheral CD4 and CD8 T cells in ROG−/− mice. A, Schematic representation of wild-type and mutant loci of the ROG gene together with the targeting vector. B, Representative Southern blot analysis with XhoI-digested DNA. C, ROG mRNA levels in ROG+/+, ROG+/−, and ROG−/− thymocytes and splenic T cells were determined by means of quantitative RT-PCR. D, Representative CD4/CD8 profiles of thymocytes and splenocytes of ROG−/− mice. The yields of thymocytes and splenocytes are shown with standard deviations (lower panel). E, The phenotypic features of splenic CD4 and CD8 T cells from ROG−/− mice. Each histogram depicts the expression of the indicated maker antigens on electronically gated splenic CD4 or CD8 T cells. Background staining is shown in shaded areas. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Experimental protocols for antigen sensitization, challenge, and assay in the different mouse models. A, BALB/c and C57BL/6 mice were injected intraperitoneally with 250 μg of OVA in 4 mg of aluminum hydroxide gel on days 0 and 7. Mice were then treated with aerosolized OVA in saline (10 mg/mL) by means of inhalation on days 14, 16, 21, and 23 (challenge). On day 24, AHR and lung resistance (RL) were assessed. On day 25, BAL fluid cells were prepared. Samples for histologic analysis were prepared on day 25. B, On day 0, retrovirus-mediated ROG-overexpressing cells (1 × 106) were transferred into BALB/c nu/nu mice. After cell transfer, the mice were treated with aerosolized OVA in saline (10 mg/mL) by means of inhalation on days 2 and 4. No OVA immunization was performed. RL was measured and BAL fluid was collected on day 6. C, Donor mice (ROG−/− and ROG Tg mice on a C57Bl/6 background) and recipient mice (C57BL/6) were sensitized intraperitoneally with 250 μg of OVA with alum on days 0 and 7. On day 14, splenic CD3 T cells were prepared from donor mice and transferred into recipient mice. The recipient mice were treated with aerosolized OVA in saline (10 mg/mL) by means of inhalation on days 16 and 18. BAL fluid was collected on day 19. Samples for histologic analysis were prepared on day 19. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

ROG+/+ and ROG−/− mice were sensitized with OVA and underwent inhalation challenge of OVA or PBS. A, Semiquantitative analysis of the abundance of PAS-positive mucus-containing cells. ∗P < .01, Student t test. B, One day after the last OVA inhalation, AHR in response to increasing doses of methacholine was measured in a whole-body plethysmograph. Mean enhanced pause (Penh) values (6 mice per group) are shown with SDs. Three independent experiments were performed, and similar results were obtained. ∗P < .01, Kruskal-Wallis test. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Enhanced proliferative responses in ROG−/− T cells Enhanced proliferative responses in ROG−/− T cells. A, Splenic CD4 and CD8 T cells from ROG−/− mice were stimulated with indicated doses of immobilized anti-TCRβ mAb (3 μg/mL) for 2 days, and proliferative response was assessed. Mean tritiated thymidine incorporation in each culture is shown with SDs. B, Splenic CD4 T cells from ROG−/− x DO11.10 Tg mice or CD8 T cells from ROG−/− x OT-I Tg mice were labeled with carboxyfluorescein succinimidyl ester and were stimulated with antigenic peptide (0.1 μmol/L) plus irradiated APCs (Thy1.2-negative cells) in the presence of IL-2 (25 U/mL) for 48 hours. C, Splenic CD4 T cells from ROG−/− x DO11.10 Tg mice were stimulated with indicated doses of antigenic peptide and irradiated BALB/c APCs (Thy1.2-negative cells) for 2 days, and antigenic peptide–induced proliferative response was assessed. Mean tritiated thymidine incorporation in each culture is shown with SDs. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Increased TH2 cell differentiation of ROG−/− T cells under neutral conditions in vitro. Naive (CD44low) CD4 T cells from ROG−/− x DO11.10 Tg mice were purified by means of cell sorting and stimulated with indicated doses of antigenic peptide plus irradiated APCs (Thy1.2-negative cells) under neutral conditions for 5 days. The results are representative of 5 experiments. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Increased numbers of IL-4–producing cells in the draining lymph nodes of ROG−/− mice. ROG+/+ and ROG−/− mice were sensitized and challenged by means of OVA inhalation. Mediastinal lymph nodes were collected 48 hours after the last OVA inhalation. Intracellular staining profiles of IFN-γ and IL-4, after stimulation with phorbol 12-myristate 13-acetate (10 ng/mL) and ionomycin (1 μmol/L) for 4 hours, are shown with the percentage of cells in each area. Lymph node cells from 5 ROG+/+ and 6 ROG−/− mice were pooled before stimulation. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Phenotypic characterization of thymocytes and peripheral CD4 and CD8 T cells in ROG Tg mice. A, Schematic representations of the construct used for T cell–specific Tg expression of ROG. B, Representative Southern blot analysis with HindIII-degested DNA. C, ROG mRNA levels in ROG Tg thymocytes, splenic CD4 T cells, and splenic CD8 T cells were determined by means of quantitative RT-PCR. ∗P < .01, Student t test. D, Representative CD4/CD8 profiles of thymocytes and splenocytes of ROG Tg mice are shown. The yields of thymocytes and splenocytes are shown with SDs (D, lower panel; n = 7). E, The phenotypic features of splenic CD4 and CD8 T cells from ROG Tg mice are shown. WT, Wild-type. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

ROG Tg mice were sensitized with OVA and underwent inhalation challenge with OVA or PBS. A, Semiquantitative analysis of the abundance of PAS-positive mucus-containing cells shown in Fig E3, A. ∗P < .01, Student t test. B, AHR was measured in a whole-body plethysmograph. Three independent experiments were performed, and similar results were obtained. ∗P < .01, Kruskal-Wallis test. WT, Wild-type. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Splenic CD4 and CD8 T cells from ROG Tg mice exhibited poor proliferative responses. A, Splenic CD4 and CD8 T cells from ROG Tg mice were stimulated with indicated concentrations of immobilized anti-TCRβ mAb (3 μg/mL) for 2 days, and proliferative response was assessed. B, Splenic CD4 T cells from ROG Tg x OT-II Tg mice were stimulated with indicated doses of antigenic peptide and irradiated C57BL/6 APCs (Thy1.2-negative cells) for 2 days. Journal of Allergy and Clinical Immunology 2008 122, 512-520.e11DOI: (10.1016/j.jaci.2008.06.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions