Immuno-Biology Lab, Translational Health Science and Technology Institute, Faridabad, India.
Front Immunol. 2019 May 20;10:1120. doi: 10.3389/fimmu.2019.01120. eCollection 2019.
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.
白细胞介素 9（IL-9）产生的辅助性 T（Th9）细胞在诱导过敏炎症、自身免疫、细胞外病原体免疫和抗肿瘤免疫反应方面具有关键的效应功能。虽然已经确定了导致人类 Th9 细胞分化的细胞因子，但尚未确定支持 Th9 细胞分化的其他因素。在这里，我们表明细胞外三磷酸腺苷（eATP）诱导 Th9 细胞的分化。我们进一步表明，eATP 诱导一氧化氮（NO）的产生，在人类 Th9 细胞的分化中形成一个正反馈环，因为嘌呤能受体信号的抑制抑制了人类 Th9 细胞的生成，而外源性 NO 即使在抑制嘌呤能受体信号的情况下也可以挽救 Th9 细胞的生成。此外，我们表明 ATP 促进 mTOR 和 HIF1α 依赖的 Th9 细胞生成。因此，我们的研究结果表明，ATP 诱导的一氧化氮增强了 HIF1α 介导的代谢途径，导致 Th9 细胞中 IL-9 的诱导。在这里，我们确定了 ATP-NO-mTOR-HIF1α 轴对于人类 Th9 细胞的产生是必不可少的，并且对该轴的调节可能导致 Th9 相关疾病状况的治疗干预。
