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

Nat Commun. 2016 Mar 3:7:10857. doi: 10.1038/ncomms10857.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation / physiology*
  • Female
  • Gene Expression Regulation / physiology
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism*
  • Lung Diseases / chemically induced
  • Male
  • Mice
  • Mice, Knockout
  • Papain / toxicity
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*

Substances

  • Interferon Regulatory Factors
  • Interleukin-2
  • interferon regulatory factor-4
  • Protein Kinases
  • Smok1 protein, mouse
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase
  • Papain