title: GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma.
abstract: BACKGROUND
  Allergic asthma is characterized by airway hyperresponsiveness (AHR) and allergic inflammation of the airways, driven by allergen-specific Th2 cells. The asthma phenotypes and especially AHR are sensitive to the presence and activity of regulatory T (Treg) cells in the lung. Glucocorticoid-induced tumor necrosis factor receptor (GITR) is known to have a co-stimulatory function on effector CD4+ T cells, rendering these cells insensitive to Treg suppression. However, the effects of GITR signaling on polarized Th1 and Th2 cell effector functions are not well-established. We sought to evaluate the effect of GITR signaling on fully differentiated Th1 and Th2 cells and to determine the effects of GITR activation at the time of allergen provocation on AHR and airway inflammation in a Th2-driven mouse model of asthma.
  
  
  METHODS
  CD4+CD25- cells were polarized in vitro into Th1 and Th2 effector cells, and re-stimulated in the presence of GITR agonistic antibodies to assess the effect on IFNgamma and IL-4 production. To evaluate the effects of GITR stimulation on AHR and allergic inflammation in a mouse asthma model, BALB/c mice were sensitized to OVA followed by airway challenges in the presence or absence of GITR agonist antibodies.
  
  
  RESULTS
  GITR engagement potentiated cytokine release from CD3/CD28-stimulated Th2 but not Th1 cells in vitro. In the mouse asthma model, GITR triggering at the time of challenge induced enhanced airway hyperresponsiveness, serum IgE and ex vivo Th2 cytokine release, but did not increase BAL eosinophilia.
  
  
  CONCLUSIONS
  GITR exerts a differential effect on cytokine release of fully differentiated Th1 and Th2 cells in vitro, potentiating Th2 but not Th1 cytokine production. This effect on Th2 effector functions was also observed in vivo in our mouse model of asthma, resulting in enhanced AHR, serum IgE responses and Th2 cytokine production. This is the first report showing the effects of GITR activation on cytokine production by polarized primary Th1 and Th2 populations and the relevance of this pathway for AHR in mouse models for asthma. Our data provides crucial information on the mode of action of the GITR signaling, a pathway which is currently being considered for therapeutic intervention.
authors.affiliation: Laboratory of Allergology and Pulmonary diseases, Department of Pathology and Medical Biology, University Medical Centre Groningen (UMCG), Groningen University, Groningen, The Netherlands. Alexandre.Motta@unilever.com
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Motta
authors.forename: Joost L M
authors.initials: JL
authors.lastname: Vissers
authors.forename: Renée
authors.initials: R
authors.lastname: Gras
authors.forename: Betty C A M
authors.initials: BC
authors.lastname: Van Esch
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: Van Oosterhout
authors.forename: Martijn C
authors.initials: MC
authors.lastname: Nawijn
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D011657:Pulmonary Eosinophilia / Q000276:immunology; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C106544:Tnfrsf18 protein, mouse; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin