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

Abstract

Abstract A major function of the immune system is to mount specific responses to pathogens, while minimizing self-reactivity. To help orchestrate this, CD4+ T cells differentiate into distinct effector cell populations. Among these, T helper 9 (Th9) cells produce IL-9, a cytokine important for the eradication of type-II-inducing pathogens; however IL-9 has been also implicated in allergic asthma and autoimmunity. 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 vivo and in vitro. In a papain-induced model of allergic lung disease, Itk-deficient mice have reduced pulmonary inflammation and decreased IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, naïve Itk−/− CD4+ T cells essentially fail to produce IL-9 and have reduced levels of IRF4, a critical transcription factor for effector T-cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or expression of constitutively-active STAT5, but not NFATc1. We further find that STAT5 binds the Irf4 promoter, indicating one mechanism by which IL-2 can rescue weakly-activated T cells. Interestingly, while naïve WT CD4 T cells cultured in presence of the Itk inhibitor do not produce IL-9, addition of IL-2 leads to paradoxically high levels of IL-9, suggesting complex effects of Itk inhibitors that may prevent their use as therapeutics. Thus, inhibiting Itk as a therapeutic strategy for treating or preventing symptoms of asthma and other diseases in which IL-9 participates still remains an important and complex question.