Zou Xinkai, Wang Keyue, Deng Yujun, Guan Pengbo, Pu Qianlun, Wang Yuemeng, Mou Jun, Du Yizhou, Lou Xiaoxian, Wang Sijiao, Jiang Na, Zhou Shengtao, Wang Hui, Du Dan, Liu Xindong, Hu Hongbo, Zhang Huiyuan
Center for Immunology and Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Center for Immunology and Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network West China Hospital, Sichuan University, Chengdu 610041, China.
Immunity. 2024 Dec 10;57(12):2808-2826.e8. doi: 10.1016/j.immuni.2024.11.001. Epub 2024 Nov 27.
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 TCF1Ly108 stem-like Th2 cells to the ST2CD25 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 (PIP) 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.
辅助性T细胞2（Th2细胞）协调针对寄生虫感染的免疫反应并促进组织修复，但会促进哮喘和组织纤维化中的病理过程。在此，我们研究了驱动Th2细胞致病性分化的机制。对哮喘和慢性鼻窦炎患者的CD4 T细胞进行单细胞分析发现，Th2细胞中缺氧诱导因子（HIF）2α表达较高。在小鼠中，HIF2α缺陷会损害Th2细胞分化并减轻哮喘炎症。单细胞和谱系追踪方法描绘了一条从TCF1Ly108干细胞样Th2细胞到ST2CD25致病性子代的分化轨迹，这取决于一个通过对肌醇多磷酸多激酶（IPMK）进行转录调控来调节磷脂代谢和T细胞受体（TCR）-磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（AKT）激活的HIF2α-GATA3回路。在HIF2α缺陷细胞中过表达IPMK可促进磷脂酰肌醇（3,4,5）-三磷酸（PIP）合成和致病性Th2细胞分化，而对HIF2α的药理学抑制则会损害Th2细胞的致病性分化并减轻气道炎症。我们的研究结果为促进Th2介导的病理过程的背景线索提供了见解，并表明HIF2α是哮喘的一个治疗靶点。
