间质细胞
干细胞
生物
肺
免疫系统
免疫学
病理
癌症研究
细胞生物学
医学
内科学
作者
Chaoqun Wang,Ben Hyams,Nancy C. Allen,Kelly M. Cautivo,Kiara Monahan,Minqi Zhou,Madelene W. Dahlgren,Carlos Lizama,Michael A. Matthay,Paul J. Wolters,Ari B. Molofsky,Tien Peng
出处
期刊:Immunity
[Elsevier]
日期:2023-03-01
卷期号:56 (3): 576-591.e10
被引量:15
标识
DOI:10.1016/j.immuni.2023.01.032
摘要
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.
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