title: Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33.
abstract: BACKGROUND
  Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear.
  
  
  OBJECTIVE
  Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells.
  
  
  METHODS
  The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16.
  
  
  RESULTS
  RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendritic cells that was dependent on the innate cytokine thymic stromal lymphopoietin (TSLP) and also induced another innate cytokine, IL-33. Inhibiting each of these pathways allowed the natural development of Treg cells while minimizing TH2 differentiation and restored tolerance in the face of RV1B infection. In accordance, RV16 infection of human lung epithelial cells upregulated TSLP and IL-33 expression.
  
  
  CONCLUSIONS
  These results suggest that infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of TSLP, IL-33, and OX40 ligand and that this can lead to susceptibility to asthmatic lung inflammation.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mehta
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.affiliation: Veterans Medical Research Foundation, University of California San Diego, La Jolla, Calif; Department of Medicine, University of California San Diego, La Jolla, Calif.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Doerner
authors.affiliation: Airway Inflammation Research Group, Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Traves
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, Calif.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.affiliation: Airway Inflammation Research Group, Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Proud
authors.affiliation: Veterans Medical Research Foundation, University of California San Diego, La Jolla, Calif; Department of Medicine, University of California San Diego, La Jolla, Calif.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Zuraw
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif. Electronic address: mick@lji.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004847:Epithelial Cells; D006801:Humans; D007108:Immune Tolerance; D018793:Interleukin-13 / Q000276:immunology; D000067596:Interleukin-33 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D008168:Lung / Q000166:cytology; D008562:Membrane Glycoproteins / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053278:OX40 Ligand; D010047:Ovalbumin / Q000276:immunology; D010850:Picornaviridae Infections / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology; D012229:Rhinovirus; D013601:T-Lymphocytes / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000941:Antigens; D016207:Cytokines; D018793:Interleukin-13; D000067596:Interleukin-33; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D015847:Interleukin-4; D010047:Ovalbumin; D000094632:Thymic Stromal Lymphopoietin
keywords: Asthma; OX40 ligand; RV16; RV1B; epithelial cell; peripherally induced regulatory T cell; thymic stromal lymphopoietin