Abstract
Interleukin 9 (IL-9)-producing helper T (Th9) cells have a crucial effector function in inducing allergic inflammation, autoimmunity, immunity to extracellular pathogens and anti-tumor immune responses. Although the cytokines that lead to the differentiation of human Th9 cells have been identified, other factors that support the differentiation of Th9 cells have not been identified yet. Here we show that the extracellular ATP (eATP) induces the differentiation of Th9 cells. We further show that eATP induces the production of nitric oxide (NO), which create a feed forward loop in the differentiation of human Th9 cells, as inhibition of purinergic receptor signaling suppressed the generation of human Th9 cells while exogenous NO could rescue generation of Th9 cells even upon inhibition of purinergic receptor signaling. Moreover, we show that ATP promotes mTOR and HIF1α dependent generation of Th9 cells. Our findings thus identify that ATP induced nitric oxide potentiate HIF1α-mediated metabolic pathway that leads to IL-9 induction in Th9 cells. Here we identified that the ATP-NO-mTOR-HIF1α axis is essential for the generation of human Th9 cells and modulation of this axis may lead to therapeutic intervention of Th9-associated disease conditions.
Highlights
Interleukin (IL) 9, a pleotropic cytokine, was initially described as T cell growth factor, as it signals through common gamma chain on T cells [1, 2]
As compared to other effector T cell subsets, Interleukin 9 (IL-9)-producing Th9 cells are found to be less well-characterized, though the cytokines and transcription factors that leads to the induction of human Th9 cells are identified [20, 43,44,45], the role of other environmental factors, such as metabolites in the differentiation of Th9 cells are yet to be identified
In this study we have shown the extracellular ATP induces the differentiation of Th9 cells, as inhibition of purinergic receptor signaling suppressed the generation of human Th9 cells
Summary
Interleukin (IL) 9, a pleotropic cytokine, was initially described as T cell growth factor, as it signals through common gamma chain on T cells [1, 2]. In addition to T cells, the role of IL-9 was demonstrated as mast cell growth factor [3]. Upon binding to IL-9 receptor, IL-9 induces effector functions and activates mast cells, eosinophils during allergic inflammation [5, 6]. The most precise role of IL-9 was found to be associated with human allergic inflammation, both IL-9 and IL-9R was found to be genetically linked to human asthma [7]. Subsequent studies have shown that neutralization of IL-9 with anti-IL-9 antibody reduced the allergic inflammation in animal model of asthma, suggesting an important role of IL-9 in disease pathogenesis [7]. Pulmonary overexpression of IL-9 was found to enhance immunopathology in allergic inflammation in asthma in mice [8]
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