Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology Carla P. Jones, PhD, Lisa G. Gregory, PhD, Benjamin Causton, BSc, Gaynor A.

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Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology Carla P. Jones, PhD, Lisa G. Gregory, PhD, Benjamin Causton, BSc, Gaynor A. Campbell, PhD, Clare M. Lloyd, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 4, Pages 1000-1010.e3 (April 2012) DOI: 10.1016/j.jaci.2011.12.965 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Identification of in vivo generated TH9 cells. A, Number of TH9 cells in PBMCs from nonallergic and allergic donors. B, Correlation between the number of circulating TH9 cells and plasma IgE levels in humans. C, Percentage of freshly isolated human TH9 cells expressing PU.1. D, TH9 and TH2 cells in the lungs of mice challenged with PBS or HDM for up to 3 weeks. E, Phenotype of murine in vivo generated TH9 cells after 1 week of HDM challenge. F, Allergen specificity of in vivo generated pulmonary T cells. G, Percentage of TH9 cells expressing PU.1 following 1-week HDM challenge in mice. Data shown represent means ± SEMs. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Induction of TH9 differentiation in vitro by activin A. A, TH9 cells generated in the presence of IL-4 alone or in association with TGF-β1, activin A, and/or IL-25. B, Percentage of TH9 cells plotted in a histogram. C, Phenotype of TH9 cells differentiated in the presence of IL-4 with either TGF-β1 or activin A. D, IL-9 secretion from activin A–derived TH9 cells after 4 days in culture in the presence of 0.1 ng/mL of TGF-β1. Data shown represent means ± SEMs. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TH9 Adoptive transfer induces mast cell recruitment to the lungs. A, Schematic of experimental protocol. B, Total cells recovered from the lung 1 week after TH9 cell transfer and challenge with either PBS or HDM. Eosinophils (Siglec F+) (C) and TH2 cells (D) recovered from the lung. Serum mMCP-1 levels (E) and intraepithelial mast cell numbers (F) scored in lung sections expressed as total number of mouse tryptase beta 1 positive cells per lung section. G, Serum IgE levels. IL-13 (H) and IL-9 (I) levels in supernatants from HDM-stimulated LN cell cultures. J, Total cells recovered from the lungs of SCID mice adoptively transferred with TH9 cells and treated with either PBS or HDM. Serum mMCP-1 levels (K) and intraepithelial mast cells numbers (L) in SCID mice. Data shown represent means ± SEMs. ∗P < .05. LN, Lymph node; mMCP-1, mouse mast cell protease-1; NS, not significant; SCID, severe combined immunodeficiency. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Acute blockade of TGF-β and activin A inhibits TH9 differentiation. A, Schematic of experimental protocol. B, TH9 cells recovered from the lung after treatment with either anti–TGF-β and/or anti–activin A in mice challenged with either PBS or HDM. Total cells (C), lung eosinophils (D), and TH2 cells (E) recovered from the lung. Serum mMCP-1 levels (F) and intraepithelial mast cells (G) per lung section. IL-9 (H) and IL-13 (I) levels in supernatants from lymph node cell cultures. J, IL-25 levels in the lungs. Data shown represent means ± SEMs. ∗P < .05. mMCP-1, Mouse mast cell protease-1. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Chronic blockade of TGF-β and activin A reduces airway remodeling. A, Schematic of experimental protocol. B, Peribronchial and perivascular cellular infiltrate (H&E), purple-colored mucin-containing cells in the epithelium (PAS), and perivascular and peribronchiolar collagen (sirrius red) and brown stained intraepithelial mast cells. Original magnification ×40. Scale bar = 50 μm. C, Quantification of mucus positive cells. D, Intraepithelial mast cells per lung section. E, Serum mMCP-1 levels. F, Total lung collagen. G, Total cells recovered from BAL and lung. H, IL-25 levels in the lung. I, Airway resistance (RI) following 3-week HDM challenge. Data shown represent means ± SEMs. ∗P < .05. BAL, Bronchoalveolar lavage; MCPT7, mouse tryptase beta 1; mMCP-1, mouse mast cell protease-1; PAS, periodic acid-Schiff. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Identification of in vivo generated TH9 cells. A, Representative flow cytometry plot showing IL-9 production by CD4+ cells in the lung after 1 week of HDM challenge or PBS treatment. TH9 cells were defined as CD4+ lymphocytes secreting IL-9 (but not IFN-γ, IL-17, or IL-13). B, Representative flow cytometry plot showing IL-9 isotype control staining. C, Representative flow cytometry plots of NK cells, regulatory T cells, and TH17 cells isolated from the lung following 1 week of intranasal challenge with HDM. These cells do not coexpress IL-9 in response to allergen challenge after 1 week. n = 6. Data are representative of 2 independent experiments. NK, Natural killer. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 HDM challenge increases TGF-β1, IL-25, and activin A levels. A, Histogram overlay of TH9 cells. B, Levels of TGF-β1, activin A, and IL-25 in lung homogenates after 1 week of either PBS or HDM challenge were measured by ELISA. Data represents means ± SEMs from 3 independent experiments (n = 5-8). ∗P < .05. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Adoptive transfer of TH9 cells into BALB/c or SCID mice. A, Representative flow cytometry plot of CD4+IL-13−IL-10−IL-9+ cells before injection into BALB/c mice. B, Representative lung section showing TH9 cells labeled with the cell tracker DIL, around the airways. C, Total cells recovered from the lung from BALB/c mice 1 week after transfer of 106 TH2 control cells and challenge with either PBS or HDM. Eosinophils (Siglec F+) recovered from the lung as determined by flow cytometry. IL-13 and IL-9 levels were measured by ELISA from LN cell cultures stimulated with HDM for 4 days. Serum mMCP-1 levels and intraepithelial mast cell numbers scored in lung sections immunostained with the murine mast cell marker MCPT7 and expressed as total number of MCPT7 positive cells per lung section. Data shown represent means ± SEMs of 2 independent experiments (n = 4-8). D, Representative flow cytometry plot of CD3+CD4+ cells recovered from the lungs and LNs of SCID mice adoptively transferred with either TH2 or TH9 cells and treated with HDM. ∗P < .05. LN, Lymph node; mMCP-1, mouse mast cell protease-1; SCID, severe combined immunodeficiency. Journal of Allergy and Clinical Immunology 2012 129, 1000-1010.e3DOI: (10.1016/j.jaci.2011.12.965) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions