title: Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4.
abstract: Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk-deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk(-/-) CD4(+) T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Gomez-Rodriguez
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meylan
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Handon
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Erika T
authors.initials: ET
authors.lastname: Hayes
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Martha R
authors.initials: MR
authors.lastname: Kirby
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008171:Lung Diseases / Q000139:chemically induced; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010206:Papain / Q000633:toxicity; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007376:Interleukin-2; D010206:Papain; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000099218:Interferon Regulatory Factor-4; C403405:Smok1 protein, mouse; C080813:emt protein-tyrosine kinase