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Role of IL-4 Receptor &Alpha

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Role of IL-4 Receptor &Alpha Role of IL-4 receptor a–positive CD41 T cells in chronic airway hyperresponsiveness Frank Kirstein, PhD, Natalie E. Nieuwenhuizen, PhD,* Jaisubash Jayakumar, PhD, William G. C. Horsnell, PhD, and Frank Brombacher, PhD Cape Town, South Africa, and Berlin, Germany Background: TH2 cells and their cytokines are associated with IL-17–producing T cells and, consequently, increased airway allergic asthma in human subjects and with mouse models of neutrophilia. allergic airway disease. IL-4 signaling through the IL-4 receptor Conclusion: IL-4–responsive T helper cells are dispensable for 1 a (IL-4Ra) chain on CD4 T cells leads to TH2 cell acute OVA-induced airway disease but crucial in maintaining differentiation in vitro, implying that IL-4Ra–responsive CD41 chronic asthmatic pathology. (J Allergy Clin Immunol T cells are critical for the induction of allergic asthma. However, 2016;137:1852-62.) mechanisms regulating acute and chronic allergen-specific T 2 H Key words: responses in vivo remain incompletely understood. TH2 cell, acute allergic airway disease, chronic asthma, Objective: This study defines the requirements for IL-4Ra– cytokine receptors, IL-4, IL-13, gene-deficient mice responsive CD41 T cells and the IL-4Ra ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the Allergic asthma is a chronic inflammatory disease of the airways onset and chronic phase of experimental allergic airway disease. characterized by an inappropriate immune response to harmless Methods: Development of acute and chronic ovalbumin environmental antigens. T 2 cells regulate adaptive immune 1 H (OVA)–induced allergic asthma was assessed weekly in CD4 T responses to allergens, and their presence correlates with disease 2 cell–specific IL-4Ra–deficient BALB/c mice (LckcreIL-4Ra /lox) symptoms in human subjects and mice.1 IL-4 plays a crucial role and respective control mice in the presence or absence of IL-4 in the in vitro and in vivo differentiation of TH2 cells, suggesting or IL-13. major contributions for IL-4 and its receptor, IL-4 receptor a 2 Results: During acute allergic airway disease, IL-4 deficiency (IL-4Ra), in regulating allergic TH2 responses. However, the did not prevent the onset of TH2 immune responses and OVA- initiation and maintenance of in vivo TH2 differentiation is induced airway hyperresponsiveness or goblet cell hyperplasia, incompletely understood. The IL-4/IL-4Ra pathway is not essen- irrespective of the presence or absence of IL-4Ra–responsive tial for T 2 polarization in certain in vivo settings, and important 1 H CD4 T cells. In contrast, deficiency of IL-13 prevented allergic roles for the cytokines IL-25 and IL-33 and type 2 innate lymphoid asthma, irrespective of the presence or absence of IL-4Ra– cells (ILC2s) have been suggested.2 Several studies described 1 responsive CD4 T cells. Importantly, chronic allergic IL-4–independent TH2 differentiation in response to allergens or inflammation and airway hyperresponsiveness were dependent helminth infection.3,4 Other studies suggested that IL-4 signaling 1 on IL-4Ra–responsive CD4 T cells. Deficiency in IL-4Ra– is required for the expansion and maintenance of T 2 responses 1 H responsive CD4 T cells resulted in increased numbers of after Nippostrongylus brasiliensis infection or allergen treatment 5,6 but not for the initial TH2 differentiation. Although we and others have described IL-4Ra–independent 7,8 From the International Centre for Genetic Engineering and Biotechnology (ICGEB) and airway hyperresponsiveness (AHR), mouse models of allergic Division of Immunology, Institute of Infectious Disease and Molecular Medicine, asthma generally highlight the importance of IL-4, IL-5, IL-13, and Faculty of Health Science, University of Cape Town. the IL-4Ra/signal transducer and activator of transcription 6 signaling *Natalie E. Nieuwenhuizen, PhD, is currently affiliated with the Department of Immunology, Max Planck Institut fur€ Infektionsbiologie, Berlin. pathway for the development of allergic pathology, including airway Supported by grants from the National Research Foundation (NRF; South Africa; grant eosinophilia, goblet cell hyperplasia, and AHR. Mice deficient in no. 80747), the South African Research Chairs Initiative (SARChI; grant no. 64761), IL-4Ra showed abrogated TH2 cell differentiation and were protected the South African Medical Research Council (SAMRC; Immunology of Infectious from ovalbumin (OVA)–induced allergic airway disease.9-11 IL-4Ra Disease), and the International Centre for Genetic Engineering and Biotechnology (ICGEB; Cytokines and Diseases). is ubiquitously expressed, and we and others have successfully used Disclosure of potential conflict of interest: F. Kirstein, N. E. Nieuwenhuizen, J. mice with cell type–specific disruptions of the Il4ra gene to identify Jayakumar, and F. Brombacher have received research support from the National IL-4Ra–dependent disease symptoms mediated by airway epithelial Research Foundation (NRF) South Africa, the South African Medical Research cells,12 smooth muscle cells,11,13 and macrophages.10 The in vivo Council (SAMRC), and International Centre for Genetic Engineering and Biotech- requirements for IL-4Ra signaling on CD41 T cells in the initiation nology. W. G. C. Horsnell has received research support from NRF South Africa and of allergen-specific TH2 responses remain incompletely understood. the SAMRC. 1 Received for publication November 25, 2014; revised October 23, 2015; accepted for Furthermore, it has been shown that CD4 cells and IL-4 are required publication October 26, 2015. for chronic lung inflammation and AHR but might not be necessary Available online December 11, 2015. for chronic pathogenesis, including AHR, after acute inflammatory Corresponding author: Frank Brombacher, PhD, Program Coordinator, ICGEB, responses have resolved.14-17 Level 1 Werner and Beit South, Faculty of Health Science, University of Cape cre Town Campus, Anzio Road, Observatory, 7925 Cape Town, South Africa. E-mail: In the present study we used previously described Lck IL- 2/lox 1 18 [email protected]. Or: [email protected]. 4Ra mice with a CD4 T cell–specific IL-4Ra disruption The CrossMark symbol notifies online readers when updates have been made to the to define whether IL-4Ra–responsive CD41 T cells and the article such as errata or minor corrections IL-4Ra ligands IL-4 and IL-13 are required for the initial 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology in vivo differentiation of an allergen-specific TH2 response and http://dx.doi.org/10.1016/j.jaci.2015.10.036 the subsequent onset of OVA-induced allergic airway disease. 1852 J ALLERGY CLIN IMMUNOL KIRSTEIN ET AL 1853 VOLUME 137, NUMBER 6 Analysis of airway and lung cell populations Abbreviations used Single-cell suspensions were prepared from lungs of individual mice and AHR: Airway hyperresponsiveness stained for intracellular cytokines, as previously described.10 Bronchoalveolar BAL: Bronchoalveolar lavage lavage (BAL)11 and lung cell composition of individual mice was FITC: Fluorescein isothiocyanate determined by means of cell-surface staining with Siglec-F–phycoerythrin ICOS: Inducible costimulator (PE), CD11c-allophycocyanin, and GR-1–fluorescein isothiocyanate (FITC) ILC2: Type 2 innate lymphoid cell for eosinophils, neutrophils, and alveolar macrophages; CD3-PE, CD4– IL-4Ra: IL-4 receptor a peridinin-chlorophyll-protein complex, and T1/ST2-FITC for T helper cells; OVA: Ovalbumin and lineage–peridinin-chlorophyll-protein complex–Cy5.5, inducible PE: Phycoerythrin costimulator (ICOS)–allophycocyanin, and T1/ST2-FITC for ILC2s. Flow cytometry was performed on a FACSCalibur flow cytometer (BD Biosciences, Erembodegem, Belgium), and data were analyzed with FlowJo version 10 1 software (TreeStar, Ashland, Ore). All antibodies were purchased from BD Furthermore, we investigated whether CD4 T cells require Biosciences or eBioscience (San Diego, Calif), except T1/ST2 (MD IL-4Ra signals to sustain a TH2-type phenotype and to promote Bioproducts, St Paul, Minn). In some experiments BAL cells were stained disease pathology during chronic allergic airway inflammation. with the Rapi-Diff Stain Set (Clinical Diagnostics CC, Johannesburg, South We found that acute allergic airway disease and TH2 differentia- Africa) and analyzed based on differential cell counts, as described tion are independent of IL-4 signaling and that IL-13 drives previously.11 airway pathology. Loss of IL-4Ra signaling on CD41 T cells resulted in increased IL-17 production and airway neutrophilia. Importantly, IL-4–responsive CD41 T cells promoted chronic Analysis of lung cytokine responses asthmatic disease. In conclusion, IL-4–responsive T helper cells Cytokine concentrations in lung tissue homogenate (1 mg/mL protein concentration) were determined by means of ELISA, according to the are dispensable for acute OVA-induced airway disease but manufacturer’s protocols (IL-4, IL-5, and IFN-g: BD Biosciences; IL-13, required to maintain chronic asthmatic pathology. IL-17, IL-25, and IL-33: R&D Systems, Minneapolis, Minn). METHODS Statistical analysis Mice P values were calculated with GraphPad Prism 4 software (GraphPad Six- to 8-week-old female mice were used in the experiments. Generation of 2 2 Software, San Diego, Calif) by using the nonparametric Mann-Whitney test LckcreIL-4Ra /lox (C.Cg-Il4ratm1Fbb/Il4ratm2Fbb-Tg[Lck-Cre]/J) mice and IL-4R /lox 2 or Kruskal-Wallis test with the Dunn posttest. Respiratory resistance and littermates on a BALB/c background
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