| First Author | Zou X | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 12 | Pages | 2808-2826.e8 |
| PubMed ID | 39609127 | Mgi Jnum | J:360990 |
| Mgi Id | MGI:7790375 | Doi | 10.1016/j.immuni.2024.11.001 |
| Citation | Zou X, et al. (2024) Hypoxia-inducible factor 2alpha promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism. Immunity 57(12):2808-2826.e8 |
| abstractText | 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)2alpha in Th2 cells. In mice, HIF2alpha 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 HIF2alpha-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 HIF2alpha-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2alpha 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 HIF2alpha as a therapeutic target in asthma. |
