美国波士顿儿童医院Talal A. Chatila及其研究团队的最新研究表明，哮喘患者调节性T细胞Notch4-GDF15通路促进组织炎症的发生。这一研究成果于2020年9月14日发表在《自然-免疫学》杂志上。

研究人员发现，在肺组织调节性T（T_reg）细胞中白介素6和STAT3转录因子依赖性的Notch4受体上调对于过敏原和颗粒物污染物导致的气道炎症是必不可少的。Notch4通过Wnt和Hippo依赖性途径将Treg细胞转化为2型和17型辅助（T_H2和T_H17）效应T细胞。Wnt激活诱导T_reg细胞中生长和分化因子15的表达，从而激活第2组先天性淋巴样细胞，这为炎症加重提供了前反馈。

哮喘患者循环T_reg细胞中Notch4、Wnt和Hippo的上调与疾病严重程度相关并且也与T_reg细胞介导的抑制作用降低有关。因此，该研究揭示了Notch4介导的免疫耐受是导致哮喘患者组织炎症持续发生的原因。

研究人员表示，阐明维持哮喘炎症的机制对于精确治疗该疾病至关重要。

附：英文原文

Title: A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma

Author: Hani Harb, Emmanuel Stephen-Victor, Elena Crestani, Mehdi Benamar, Amir Massoud, Ye Cui, Louis-Marie Charbonnier, Sena Arbag, Safa Baris, Amparito Cunnigham, Juan Manuel Leyva-Castillo, Raif S. Geha, Amirhosein J. Mousavi, Boris Guennewig, Klaus Schmitz-Abe, Constantinos Sioutas, Wanda Phipatanakul, Talal A. Chatila

Issue&Volume: 2020-09-14

Abstract: 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 (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg 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 Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

DOI: 10.1038/s41590-020-0777-3

Source: https://www.nature.com/articles/s41590-020-0777-3