title: B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance.
abstract: The recently described ICOS-B7RP-1 costimulatory pathway has been implicated in the generation of effector Th2 responses and, hence, has become an attractive therapeutic target for allergic diseases. In the present study, we used B7RP-1-deficient mice to investigate the role of B7RP-1 in the generation and maintenance of Th2 responses in a model of mucosal allergic airway inflammation. We found that exposure of B7RP-1 knockout mice to aerosolized OVA in the context of GM-CSF leads to airway eosinophilic inflammation. This response was long lasting because rechallenge of mice with the same Ag recapitulated airway eosinophilia. Moreover, significant expression of T1/ST2 on T cells and production of Th2-affiliated cytokines (IL-5, IL-4, and IL-13) and Igs (IgE and IgG1) conclusively demonstrate the generation of a Th2 response in the absence of B7RP-1. In addition, expression of two major Th2-associated costimulatory molecules-CD28 and ICOS-indicates T cell activation in the absence of B7RP-1 signaling. Finally, B7RP-1 knockout mice are resistant to the induction of inhalation tolerance as indicated by the sustained eosinophilia in the lung and IL-5 production. In summary, our results demonstrate that in a model of mucosal allergic sensitization, the ICOS-B7RP-1 pathway is redundant for the generation of Th2 responses but essential for the induction of inhalation tolerance.
authors.affiliation: Department of Pathology and Molecular Medicine, and Division of Respiratory Diseases and Allergy, Centre For Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Beata U
authors.initials: BU
authors.lastname: Gajewska
authors.forename: Anna
authors.initials: A
authors.lastname: Tafuri
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Tina
authors.initials: T
authors.lastname: Walker
authors.forename: Jill R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Theresa
authors.initials: T
authors.lastname: Shea
authors.forename: Arda
authors.initials: A
authors.lastname: Shahinian
authors.forename: Susanna
authors.initials: S
authors.lastname: Goncharova
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stämpfli
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000235:genetics* / Q000502:physiology; D018106:CD28 Antigens / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000485:Allergens; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D010047:Ovalbumin