Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4

Julio Gomez-Rodriguez (), Françoise Meylan, Robin Handon, Erika T. Hayes, Stacie M. Anderson, Martha R. Kirby, Richard M. Siegel and Pamela L. Schwartzberg ()
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Julio Gomez-Rodriguez: National Human Genome Research Institute, National Institutes of Health
Françoise Meylan: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Robin Handon: National Human Genome Research Institute, National Institutes of Health
Erika T. Hayes: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Stacie M. Anderson: National Human Genome Research Institute, National Institutes of Health
Martha R. Kirby: National Human Genome Research Institute, National Institutes of Health
Richard M. Siegel: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Pamela L. Schwartzberg: National Human Genome Research Institute, National Institutes of Health

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10857

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