title: T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation.
abstract: The cellular and molecular mechanisms driven by IL-25 and its cognate receptor IL-17RB necessary for the promotion of Th2-mediating pathogenic pulmonary inflammation remains to be defined. We have previously reported the critical role of the U-box-type E3 ubiquitin ligase Act1 (1) for the downstream signaling of the IL-17 cytokine family including the Th2-promoting cytokine IL-25 (IL-17E) (2). In this study, we report that IL-25-driven but not conventional IL-4-driven Th2 polarization and cytokine production is impaired in Act1-deficient T cells. Also, Act1 deficiency in the T cell compartment results in the abrogation of eosinophilic airway infiltration as well as airway hyperresponsiveness in mouse models of Ag-induced airway inflammation. The in vivo generation of Ag-specific Th2 cytokine-producing cells is defective in the absence of Act1 expression in T cells after OVA/aluminum hydroxide immunization. Notably, the production of OVA-specific IgG(1) but not IgG(2a) or IgE is also impaired. At the molecular level, we report that IL-25-mediated induction of Th2 master regulator GATA-3 and the transcription factor GFI-1 is attenuated in Act1-deficient T cells. Taken together, our findings indicate that Act1 expression in T cells is required for cellular and humoral Th2-mediated allergic responses and the development of airway hyperresponsiveness, in part, through Act1's function in IL-25-induced development of Th2 T cells.
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Shadi
authors.initials: S
authors.lastname: Swaidani
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bulek
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Kang
authors.forename: Muhammet Fatih
authors.initials: MF
authors.lastname: Gulen
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Yin
authors.forename: Amina
authors.initials: A
authors.lastname: Abbadi
authors.forename: Mark
authors.initials: M
authors.lastname: Aronica
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007378:Interleukins; C442281:Mydgf protein, mouse; C515963:Traf3ip2 protein, mouse