Mus musculus BALF cell scRNA-seq Raw sequence reads
T helper 2 (Th2) cells, the hub of type II immunity, are known to play crucial roles in protecting against parasite infection, and facilitating tissue repair, while dysregulation of Th2 cells attribute to autoimmune diseases such as asthma. However, it is still unclear. Here, we found that hypoxia inducible factor (HIF)2-Alpha, but not HIF1-Alpha was substantially increased in Th2 cells and ectopic expression of HIF2-Alpha reinforced Th2 cell generation. By contrast, specific depletion of HIF2-Alpha in CD4+ T cells ameliorated asthma while impairing Th2 differentiation. Furthermore, single-cell RNA/TCR sequencing analysis in combination with lineage-tracing assessment displayed the journey of Th2 cell differentiation from stem-like TCF1+ SLAMF6+ Th2 to effector-like CXCR6+ST2+CD25+ progeny. Mechanistically, HIF2-Alpha. was specified to govern this transition via transcriptionally regulating IPMK-orchestrated phospholipid metabolism and PI3K-Akt signaling axis. Inhibition of HIF2-Alpha abrogated Th2 effector fate and mitigated airway inflammation. Therefore, our results establish that the dichotomy of stemness and effector function underlies the heterogeneous Th2 responses, and reveal previously unappreciated transcriptional as well as metabolic control of Th2 fate decision via HIF2-Alpha, which might collectively provide novel therapeutic strategy to treat Th2 mediated immunopathology in asthma.