title: Cylindromatosis (Cyld) gene mutation in T cells promotes the development of an IL-9-dependent allergic phenotype in experimental asthma.
abstract: Cylindromatosis (CYLD) is a ubiquitously expressed deubiquitinating enzyme which removes activating ubiquitin residues from important signaling molecules of the NF-κB pathway. In CYLDex7/8transgenic mice, a naturally occurring short isoform (sCYLD) is overexpressed in the absence of full length CYLD, leading to excessive NF-κB activity. Herein, we investigated the impact of the CYLDex7/8mutation selectively in T cells on the development of experimental allergic airway disease induced by sensitization and challenge with ovalbumin. Compared with their wildtype littermates, mice bearing the T cell-specific mutation (CD4+CYLDex7/8) display stronger eosinophilia and mucus production in the lungs and higher IgE serum levels. The reason for these observations is excessive production of T cell-derived IL-9, a cytokine to whom allergy-promoting properties were ascribed. Consequently, blockade of IL-9 in CD4+CYLDex7/8mice alleviates the development of disease symptoms. Thus, by polarization of the T cell cytokine response, sCYLD can favor the development of allergic airway disease.
authors.affiliation: III. Medical Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Div. of Experimental Asthma Research, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Asthma Core Facility, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Maxeiner
authors.affiliation: III. Medical Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Meyer-Martin
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Anastasija
authors.initials: A
authors.lastname: Michel
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Baars
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.affiliation: Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University Medical Center, Homburg, Germany.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wehler
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: III. Medical Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Asthma Core Facility, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Dept. of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.affiliation: Asthma Core Facility, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany. Electronic address: stassenm@uni-mainz.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Institute of Pathology, Saarland University Medical Center, Homburg, Germany. Electronic address: marc.becker@uks.eu.
authors.forename: Marc
authors.initials: M
authors.lastname: Becker
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics*; D016906:Interleukin-9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009093:Mucus / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C508607:IL9 protein, human; D016906:Interleukin-9; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: Asthma; Cylindromatosis (turban tumor syndrome) gene; IL-9; Th9 cells