Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (T_reg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T_reg cells into the type 2 and type 17 helper (T_H2 and T_H17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in T_reg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating T_reg cells of individuals with asthma as a function of disease severity, in association with reduced T_reg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

阐明维持哮喘炎症的机制对于精准治疗至关重要。_{我们发现，肺组织调节性 T (T reg} ) 细胞上 Notch4 受体的白细胞介素 6 和 STAT3 转录因子依赖性上调是过敏原和颗粒物污染物促进气道炎症所必需的。Notch4通过 Wnt 和 Hippo 通路依赖机制将 T _reg细胞转变为 2 型和 17 型辅助性（T _H 2 和 T _{H 17）效应 T 细胞。}Wnt 激活诱导生长和分化因子 15 在 T _{reg中的表达}细胞，激活第 2 组先天性淋巴样细胞，为炎症加重提供前馈机制。Notch4、Wnt 和 Hippo 在哮喘患者的循环 T _reg细胞中上调，作为疾病严重程度的函数，与减少的 T _reg细胞介导的抑制有关。因此，我们的研究将 Notch4 介导的免疫耐受颠覆确定为哮喘组织炎症的基本机制。