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UKPMC Funders Group Author Manuscript J Allergy Clin Immunol UKPMC Funders Group Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2012 June 28. Published in final edited form as: J Allergy Clin Immunol. 2012 April ; 129(4): 1000–10.e3. doi:10.1016/j.jaci.2011.12.965. UKPMC Funders Group Author Manuscript UKPMC Funders Group Author Manuscript 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, and Clare M. Lloyd, PhD Leukocyte Biology Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom Abstract Background—IL-9-secreting (TH9) T cells are thought to represent a distinct T-cell subset. However, evidence for their functionality in disease is uncertain. Objective—To define a functional phenotype for TH9-driven pathology in vivo. Methods—We used fluorescence-activated cell sorting to identify circulating TH9 cells in atopic and nonatopic subjects. In mice we utilized a model of allergic airways disease induced by house dust mite to determine TH9 cell function in vivo and the role of activin A in TH9 generation. Results—Allergic patients have elevated TH9 cell numbers in comparison to nonatopic donors, which correlates with elevated IgE levels. In a murine model, allergen challenge with house dust mite leads to rapid TH9 differentiation and proliferation, with much faster kinetics than for TH2 cell differentiation, resulting in the specific recruitment and activation of mast cells. The TGF-β superfamily member activin A replicates the function of TGF-β1 in driving the in vitro generation of TH9 cells. Importantly, the in vivo inhibition of TH9 differentiation induced by allergen was achieved only when activin A and TGF-β were blocked in conjunction but not alone, resulting in reduced airway hyperreactivity and collagen deposition. Conversely, adoptive transfer of TH9 cells results in enhanced pathology. Conclusion—Our data identify a distinct functional role for TH9 cells and outline a novel pathway for their generation in vitro and in vivo. Functionally, TH9 cells promote allergic responses resulting in enhanced pathology mediated by the specific recruitment and activation of mast cells in the lungs. Keywords Activin A; TH9 cells; IL-9; asthma; allergy; mast cells; house dust mite; TGF-β IL-9, a signature cytokine involved in asthma, is secreted by a range of resident and infiltrating cells and has been described as a candidate gene during genetic linkage analysis.1,2 IL-9 is important for the development of disease pathology, particularly for the 3-5 survival and differentiation of mast cells. Although originally described as a TH2 3,6-8 cytokine, IL-9 is produced by a distinct subset of effector T cells, termed TH9 cells. These cells have been generated in vitro in an environment of IL-4 and TGF-β1,7,8 but © 2012 American Academy of Allergy, Asthma & Immunology Corresponding author: Clare M. Lloyd, PhD, Leukocyte Biology Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College, South Kensington, London SW7 2AZ, UK. [email protected]. *These authors contributed equally to this work. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. Jones et al. Page 2 direct evidence for their existence in vivo is lacking. Although TH9 cells lack expression of either T bet or GATA-3, the defining transcription factors for TH1 or TH2 lineage development, respectively, PU.1 and interferon regulatory factor 4 have both been 9,10 associated with TH9 cell differentiation. IL-25 maximizes TH9 differentiation, due to the UKPMC Funders Group Author Manuscript UKPMC Funders Group Author Manuscript expression of its receptor, interleukin-17 receptor B (IL-17RB), on the cell surface.11,12 Importantly, this pathway was shown to be important for the regulation of IL-9 expression during allergic airway inflammation, since IL-25 deficiency leads to reduced IL-9 expression and airway inflammation.13 There is a wealth of evidence to show that IL-9 is involved in the development of allergic responses.5,14,15 Many cells are able to secrete IL-9, but the specific cellular source has not 16,17 been determined in vivo. TH9 cells have been implicated in the development of disease in the central nervous system,3 the lung,10 and the eye18; however, it is not clear how they actually contribute to pathology in these organs. In particular, the specific contribution that TH9 cells might make during the development of allergic immune responses remains unclear. The TGF-β superfamily member activin A plays a vital role during allergic responses, promoting enhanced remodeling and airway hyperreactivity (AHR) via interactions with IL-25.19 This interaction between activin A and IL-25 coupled with the fact that IL-25 maximizes TGF-β1-mediated differentiation of TH9 cells prompted us to investigate the role of activin A in TH9 development. We demonstrate that activin A is able to replicate the ability of TGF-β1 to drive TH9 polarization in vitro and in vivo. Critically, effective suppression of TH9 function in vivo is entirely reliant on the blockade of both TGF-β and activin A. Our studies show that TH9 cells have an in vivo function that is distinct, but complementary to that of TH2 cells, and reveal a novel pathway to TH9 differentiation that has direct consequences for the development of allergic pathology. METHODS Mice BALB/c and severe combined immunodeficiency mice (6-8 weeks) were purchased from Charles River (Morgate, United Kingdom [UK]). All experiments were performed in accordance with UK Home Office guidelines. Induction and analysis of allergic airway inflammation Mice received 15 μg of house dust mite (HDM) extract (Dermatophagoides pteronyssinus in saline; Greer Laboratories, Lenoir, NC) or saline intranasally 3 days a week for 1 or 3 6 weeks. In adoptive transfer experiments, 1 × 10 in vitro generated TH9 cells (more than 90% CD4+IL-9+IL-13−IFN-γ−) were injected intraperitoneally. In blocking experiments, mice received 20 μg of neutralizing antibody to murine activin A (R&D Systems, Abingdon, UK) and/or anti-TGF-β (5 mg/kg, clone 1D11 pan neutralizing TGF-β1-3; Genzyme Corporation, Cambridge, Mass) or isotype control intraperitoneally. Serum, bronchoalveolar lavage fluid, lung homogenates, and draining lymph nodes were harvested as previously described.19 AHR and airway remodeling were assessed as described previously.19 TH9 cell differentiation CD3+CD4+ cells from lymph nodes and spleens were stimulated with plate-bound anti-CD3 (1 μg/mL; BD Pharmingen, Oxford, UK) plus soluble anti-CD28 (2 μg/mL; BD Pharmingen) in the presence of 5 ng/mL of rIL-4 and 1 ng/mL of rTGF-β1 or 20 ng/mL of activin A with or without rIL-25 (10 ng/mL) in IMDM (Sigma, Gillingham, UK) J Allergy Clin Immunol. Author manuscript; available in PMC 2012 June 28. Jones et al. Page 3 supplemented with 10% FCS (Life Technologies, Carlsbad, Calif). TH2 cells were differentiated with 10 μg of anti-IFNγ and 10 ng/mL of IL-4. After 4 days, cells were restimulated with 500 ng/mL of ionomycin and 50 ng/mL of phorbol 2-myristate 13-acetate in the presence of brefeldin (BD Pharmingen). Cells were stained for CD4, PU.1 (Cell UKPMC Funders Group Author Manuscript UKPMC Funders Group Author Manuscript Signalling Technology, Beverly, Mass), IL-13, IL-10, IL-17, IFN-γ (BD Pharmingen), or + + − − IL-9 (Biolegend, San Diego, Calif). TH9 cells are defined as CD4 IL-9 IL-13 IFN-γ cells. + + TH2 cells are defined as CD4 IL-13 . For the detection of IL-17RB surface expression, T cells were stained with anti-IL-17RB, followed by anti-rabbit IgG Alexa488 (Invitrogen, Paisley, UK). Cells from the lung were additionally stained with the following antibodies: anti-GR1, anti-SiglecF (BD Pharmingen), anti-mouse T1/ST2 (Morwell Diagnostics, Zurich, Switzerland), or relevant isotype controls. Labeled cells were acquired on the BD fluorescence-activated cell sorting Aria (BD Bioscience, Oxford, UK) and further analyzed by using FlowJo (Treestar, Ashland, Ore). An equal number of total events were collected for analysis. Cytokine analysis Paired antibodies for murine IL-4, IL-5, TGF-β1, and IFN-γ (BD Pharmingen) and IL-25, activin A, IL-33, IL-13 thymic stromal lymphopoietin, CCL20, and IgE (R&D Systems, Minneapolis, Minn) were used in standardized sandwich ELISAs. Human IL-9 ELISA kit was purchased from Peprotech (Rocky Hill, NJ). All presented data have been normalized for tissue weight. Mouse mast cell protease-1 (Moredun, Penicuik, UK) was used according to the manufacturer’s protocol. Immunohistochemistry Paraffin sections were stained with rabbit anti-mouse tryptase beta 1 (Abcam, Cambridge, UK). Intraepithelial mast cells were scored in the whole lung section (normalized for area), and median of the numbers of intraepithelial mast cells/section was reported. Quantification of total lung collagen Recently synthesized acid-soluble collagens were measured in lung tissue by biochemical assay according to the manufacturer’s instructions (Sircol collagen assay; Biocolor, Belfast, UK). Human TH9 cells The study was approved by the ethics committee of the Royal Brompton and Harefield Hospitals NHS Trust and was performed with the subjects’ written informed consent. Whole blood (50 mL) was collected for the isolation of PBMCs and the measurement of serum IgE level by ELISA. Atopic subjects had self-reported allergies to either pollen or HDM or both. Only those individuals who had not used mediation to treat symptoms of allergy for 4 weeks prior to blood sampling were included in the study. Atopic status was confirmed by elevated serum IgE levels. PBMCs were stimulated as before and analyzed for the expression of PU.1 (Cell Signaling Technology), IL-13, INF-γ, and IL-9 (BD Pharmingen).
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