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, Pamela L Schwartzberg

Nature communications 2016

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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.

Citation

Julio Gomez-Rodriguez, Françoise Meylan, Robin Handon, Erika T Hayes, Stacie M Anderson, Martha R Kirby, Richard M Siegel, Pamela L Schwartzberg. Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nature communications. 2016;7:10857