Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2⁺ conventional DC2 subset (cDC2s) that induces regulatory T cells (T_regs) maintaining lung tolerance at steady state but promotes T_H2 response during house dust mite (HDM)–induced asthma. Lung IFNβ is essential for TNFR2⁺ cDC2s–mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed T_H2-promoting pathogenic TNFR2⁺ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2⁺ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung T_reg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2⁺ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.

哮喘是一种常见的炎症性肺病，目前尚无治愈方法。此前，我们发现了一种肺 TNFR2 ⁺常规 DC2 亚群 (cDC2s)，它诱导调节性 T 细胞 (T _regs ) 在稳定状态下维持肺耐受性，但在屋尘螨 (HDM) 诱导的哮喘期间促进 T _{H 2 反应。}肺 IFNβ 对于 TNFR2 ⁺ cDC2s 介导的肺耐受性至关重要。在这里，我们发现外源性 IFNβ 将促进 T _H 2 的致病性 TNFR2 ⁺ cDC2 重编程为耐受性 DC，从而缓解嗜酸性哮喘并预防哮喘恶化。机制上，吸入 IFNβ，而不是 IFNα，激活了致病性肺 TNFR2 ^{+中的 ERK2 信号传导}cDC2s，导致增强的脂肪酸氧化 (FAO) 和肺 T _reg诱导。最后，人 IFNβ 对来自肺气肿患者的致病性人肺 TNFR2 ⁺ cDC2 进行了离体重编程。因此，我们确定了可用于 DC 治疗的 IFNβ 特异性 ERK2-FAO 途径。