T helper 2 (Th2) cells orchestrate immunity against parasite infection and promote tissue repair but promote pathology in asthma and tissue fibrosis. Here, we examined the mechanisms driving pathogenic differentiation of Th2 cells. Single-cell analyses of CD4+ T cells from asthma and chronic rhinosinusitis patients revealed high expression of the hypoxia-inducible factor (HIF)2α in Th2 cells. In mice, HIF2α deficiency impaired Th2 differentiation and alleviated asthmatic inflammation. Single-cell and lineage tracing approaches delineated a differentiation trajectory from TCF1+Ly108+ stem-like Th2 cells to the ST2+CD25+ pathogenic progeny, depending on a HIF2α-GATA3 circuit that modulated phospholipid metabolism and T cell receptor (TCR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) activation via transcriptional regulation of the inositol polyphosphate multikinase (IPMK). Overexpression of IPMK in HIF2α-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2α impaired pathogenic differentiation of Th2 cells and mitigated airway inflammation. Our findings provide insight into the contextual cues that promote Th2-mediated pathology and suggest HIF2α as a therapeutic target in asthma.

中文翻译：

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缺氧诱导因子 2α 通过调节磷脂代谢促进干细胞样 Th2 细胞的致病性极化


辅助性 T 细胞 2 （Th2） 协调对寄生虫感染的免疫力并促进组织修复，但促进哮喘和组织纤维化的病理学。在这里，我们研究了驱动 Th2 细胞致病性分化的机制。对哮喘和慢性鼻-鼻窦炎患者 CD4+ T 细胞的单细胞分析显示，缺氧诱导因子 （HIF）2α 在 Th2 细胞中高表达。在小鼠中，HIF2α 缺陷损害了 Th2 分化并减轻了哮喘炎症。单细胞和谱系示踪方法描绘了从 TCF1+Ly108+ 干细胞样 Th2 细胞到 ST2+CD25+ 致病后代的分化轨迹，具体取决于调节磷脂代谢的 HIF2α-GATA3 回路和 T 细胞受体 （TCR）-磷脂酰肌醇 3-激酶 （PI3K）-蛋白激酶 B （AKT） 通过肌醇多磷酸多激酶 （IPMK） 的转录调节激活。在 HIF2α 缺陷细胞中过表达 IPMK 促进了磷脂酰肌醇 （3,4,5）-三磷酸 （PIP3） 的合成和致病性 Th2 细胞分化，而 HIF2α 的药理学抑制损害了 Th2 细胞的致病性分化并减轻了气道炎症。我们的研究结果提供了对促进 Th2 介导病理学的背景线索的见解，并表明 HIF2α 是哮喘的治疗靶点。