ID2 Unlocks retinoic acid signaling to promote eosinophil maturation by antagonizing TCF3

Novel functions of eosinophils are continually being discovered, yet the regulatory mechanisms underlying eosinophil development-particularly how ubiquitous nutrient metabolites integrate with cell-intrinsic transcriptional programs-remain poorly defined. Using zebrafish and mouse models, we demonstrate that ID2 promotes eosinophil maturation by orchestrating retinoic acid (RA) signaling. We show that ID2 interacts with and inhibits TCF3, thereby relieving TCF3-mediated suppression of Rarg expression and ensuring adequate RA signaling to support eosinophil maturation. Our findings reveal the critical role of the ID2-TCF3-RARγ axis in eosinophil development, illustrating a coordinated regulatory mechanism involving RA signaling and ID2 during eosinophilopoiesis. This study elucidates how nutrient-derived signals are finely tuned during eosinophil lineage development, providing insights for RA-related treatments and dietary interventions in homeostasis and eosinophil-associated diseases.