Notch2 Directs aTreg Cell Fate toward Immunoregulation or Inflammatory Pyroptosis

Schematic illustration showing that the Notch2 intracellular domain (NICD2) facilitates pyroptosis resistance in activated Tregs through the RREB1/Foxo1 signaling pathway. In addition, Notch2‐mediated pyroptosis resistance in activated Tregs promotes immunoregulatory capacity, thereby attenuating Th2‐driven inflammatory responses in allergic rhinitis (AR). (AS1842856: Foxo1‐specific inhibitor). ABSTRACT Activated regulatory T cells (aTregs) exhibit potent immunosuppressive functions and can migrate to tissues, playing a crucial role in attenuating inflammatory responses. The precise role and molecular mechanisms through which Notch2 regulates the immunoregulatory functions of aTregs remain incompletely elucidated. Here, we elucidate the mechanisms through which Notch2 influences aTreg dynamics and mitigates allergic rhinitis (AR) development. Mechanistically, the targeted knockout of Notch2 in aTregs resulted in decreased Foxo1 expression and elevated phosphorylated ASC (p‐ASC) levels, culminating in GSDMD‐N‐mediated pyroptosis in aTregs. Moreover, the Notch2 intracellular domain (NICD2) promoted the nuclear translocation of RREB1 through direct protein–protein interactions, thereby enhancing Foxo1 transcriptional activity. Importantly, the adoptive transfer of Notch2+ aTregs significantly reduced Th2 inflammatory responses in AR mice, providing an effective therapeutic strategy for managing AR‐related inflammation. Overall, our findings establish a novel paradigm in the pathogenesis of AR in which Notch2 expression dictates the functional dichotomy of aTregs in maintaining their immunoregulatory capacity or undergoing inflammatory pyroptosis. Schematic illustration showing that the Notch2 intracellular domain (NICD2) facilitates pyroptosis resistance in activated Tregs through the RREB1/Foxo1 signaling pathway. In addition, Notch2-mediated pyroptosis resistance in activated Tregs promotes immunoregulatory capacity, thereby attenuating Th2-driven inflammatory responses in allergic rhinitis (AR). (AS1842856: Foxo1-specific inhibitor). ABSTRACT Activated regulatory T cells (aTregs) exhibit potent immunosuppressive functions and can migrate to tissues, playing a crucial role in attenuating inflammatory responses. The precise role and molecular mechanisms through which Notch2 regulates the immunoregulatory functions of aTregs remain incompletely elucidated. Here, we elucidate the mechanisms through which Notch2 influences aTreg dynamics and mitigates allergic rhinitis (AR) development. Mechanistically, the targeted knockout of Notch2 in aTregs resulted in decreased Foxo1 expression and elevated phosphorylated ASC (p-ASC) levels, culminating in GSDMD-N-mediated pyroptosis in aTregs. Moreover, the Notch2 intracellular domain (NICD2) promoted the nuclear translocation of RREB1 through direct protein–protein interactions, thereby enhancing Foxo1 transcriptional activity. Importantly, the adoptive transfer of Notch2+ aTregs significantly reduced Th2 inflammatory responses in AR mice, providing an effective therapeutic strategy for managing AR-related inflammation. Overall, our findings establish a novel paradigm in the pathogenesis of AR in which Notch2 expression dictates the functional dichotomy of aTregs in maintaining their immunoregulatory capacity or undergoing inflammatory pyroptosis. Advanced Science, EarlyView.