四川大学张惠媛等研究人员合作发现，低氧诱导因子2α通过调节磷脂代谢促进类干性Th2细胞的致病性极化。这一研究成果于2024年11月27日在线发表在国际学术期刊《免疫》上。

研究人员揭示了驱动辅助性T细胞2型（Th2）细胞致病性分化的机制。来自哮喘和慢性鼻窦炎患者的CD4⁺ T细胞的单细胞分析揭示，Th2细胞中低氧诱导因子（HIF）2α的表达较高。在小鼠中，HIF2α缺失会损害Th2细胞的分化并缓解哮喘性炎症。

单细胞和谱系追踪方法描绘了，从TCF1⁺Ly108⁺类干性Th2细胞到ST2⁺CD25⁺致病性后代的分化轨迹。这一过程依赖于HIF2α-GATA3回路，通过转录调控肌醇多磷酸酯多激酶（IPMK）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。

在HIF2α缺失的细胞中过表达IPMK促进了，磷脂酰肌醇（3,4,5）-三磷酸（PIP3）合成和致病性Th2细胞分化，而药理学抑制HIF2α则损害了Th2细胞的致病性分化，并减轻了气道炎症。该研究为理解促进Th2介导的病理变化的环境信号提供了新的见解，并建议HIF2α作为哮喘治疗的潜在靶点。

据了解，Th2细胞在抗寄生虫感染和促进组织修复中发挥重要作用，但在哮喘和组织纤维化中却促进病理变化。

附：英文原文

Title: Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism

Author: Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang

Issue&Volume: 2024-11-27

Abstract: 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.

DOI: 10.1016/j.immuni.2024.11.001

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00496-5