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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Julio Gomez-Rodriguez & Françoise Meylan & Robin Handon & Erika T. Hayes & Stacie M. Anderson & Martha R. Kirby & Richard M. Siegel & Pamela L. Schwartzberg, 2016. "Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10857
    DOI: 10.1038/ncomms10857
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    Cited by:

    1. Sang-A Park & Yun-Ji Lim & Wai Lim Ku & Dunfang Zhang & Kairong Cui & Liu-Ya Tang & Cheryl Chia & Peter Zanvit & Zuojia Chen & Wenwen Jin & Dandan Wang & Junji Xu & Ousheng Liu & Fu Wang & Alexander C, 2022. "Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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