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

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机构： [1]Center for Immunology and Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2]Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network West China Hospital, Sichuan University, Chengdu 610041, China [3]Laboratory of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu 610041, China [4]Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China [5]Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China [6]National Experimental Demonstration Center for Basic Medicine Education, Xuzhou Medical University, Xuzhou, China [7]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China [8]Chongqing International Institute for Immunology, Chongqing, China [9]Jinfeng Laboratory, Chongqing 401329, China [10]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610041, China

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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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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第一作者机构： [1]Center for Immunology and Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

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通讯机构： [1]Center for Immunology and Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [7]Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China [8]Chongqing International Institute for Immunology, Chongqing, China [9]Jinfeng Laboratory, Chongqing 401329, China [10]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610041, China

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