title: IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa.
abstract: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown.
  
  
  
  We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP.
  
  
  
  Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis.
  
  
  
  IL-25 receptor (IL-17RB)-expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB(+)CD4(+) polyp-derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB(+)CD4(+) T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17-producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells.
  
  
  
  IL-25 and IL-33 can interact locally with IL-17RB(+)ST2(+) polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.
authors.affiliation: Division of Asthma, Allergy and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Emily P S
authors.initials: EP
authors.lastname: Lam
authors.affiliation: Allergy and Medical Rhinology Section, Royal National Throat Nose Ear Hospital, University College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Harsha H
authors.initials: HH
authors.lastname: Kariyawasam
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Batika M J
authors.initials: BM
authors.lastname: Rana
authors.affiliation: Section of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Durham
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology and Medical Research Council Centre for Transplantation, King's College London, London, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Powell
authors.affiliation: Section of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Nara
authors.initials: N
authors.lastname: Orban
authors.affiliation: Division of Asthma, Allergy and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lennartz-Walker
authors.affiliation: Department of ENT, Guy's and St Thomas' Hospital, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Hopkins
authors.affiliation: Division of Asthma, Allergy and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom.
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
authors.affiliation: Allergy and Medical Rhinology Section, Royal National Throat Nose Ear Hospital, University College London, London, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Rimmer
authors.affiliation: Allergy and Medical Rhinology Section, Royal National Throat Nose Ear Hospital, University College London, London, United Kingdom.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Lund
authors.affiliation: Department of Infection, Immunity and Inflammation, NIHR Leicester Respiratory Biomedical Research Unit, Leicester Institute for Lung Health, University of Leicester, Leicester, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cousins
authors.affiliation: Division of Asthma, Allergy and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address: stephen.till@kcl.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Till
mesh_terms: D002908:Chronic Disease; D004802:Eosinophilia / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D000067596:Interleukin-33 / Q000276:immunology*; D009297:Nasal Mucosa / Q000276:immunology*; D009298:Nasal Polyps / Q000276:immunology*; D012220:Rhinitis / Q000276:immunology*; D012852:Sinusitis / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: C486701:IL25 protein, human; C506536:IL33 protein, human; D020381:Interleukin-17; D000067596:Interleukin-33
keywords: Chronic rhinosinusitis with nasal polyps; IL-17RB; IL-25; IL-33; ST2; T(H)17 cells; T(H)2 cells; T-cell phenotype; T-cell receptor Vβ repertoire; microarray; nasal mucosa