Abstract：
Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.
摘要：
遇到过敏原时，CD4+T细胞在淋巴结中分化为产生IL-4的Th2细胞，其随后转化为多功能Th2细胞,在发炎组织中产生IL-5和IL-13。然而,它们多功能性的精确机制仍然难以捉摸。在这项研究中,我们阐明了NRF2在过敏性哮喘小鼠模型和人类Th2细胞中多功能Th2细胞中的关键作用。我们发现，浸润肺部的免疫细胞中活性氧（ROS）的增加对于体内嗜酸性粒细胞哮喘和多功能Th2细胞的发展是必需的。特异性在T细胞中删除ROS传感器NRF2，但不是在树突状细胞中，显著消除气道中嗜酸性粒细胞增多和多功能Th2细胞。机械上,T细胞固有的NRF2对于诱导最佳氧化磷酸化和糖酵解能力至关重要，从而独立于IL-33驱动Th2细胞多功能性,部分通过诱导PPARγ。用NRF2抑制剂治疗导致小鼠中多功能Th2细胞的大量减少和随后的嗜酸性粒细胞增多,以及哮喘患者中外周血单核细胞产生Th2细胞因子的减少。这些发现强调了Nrf2作为空间和时间代谢中心的关键作用，这对多功能Th2细胞至关重要。提示过敏性疾病的潜在治疗意义。
