异常的组织免疫相互作用是多种慢性肺部疾病的特征。在这里，我们试图定义肺气肿中这些相互作用，这是一种以感染性恶化和肺泡上皮损失为特征的进展性疾病。人肺气肿肺部的单细胞分析显示出组织驻留淋巴细胞（TRL）的扩张。小鼠研究确定了表达Hhip的一种基质niche，这是一种在肺气肿中下调的疾病-变体基因。Hhip的基质特异性缺失通过超活跃的刺猬-IL-7轴介导的肺部组织驻留淋巴细胞的地形扩张。3D免疫干细胞器官和病毒恶化的动物模型表明，扩张的TRL通过干扰素γ（IFNγ）抑制肺泡干细胞的生长。最后，我们发现了一种IFNγ敏感的人肺泡干细胞亚群，这种亚群在肺气肿中有选择性丧失。因此，我们勾勒出肺部的基质-淋巴细胞-上皮干细胞轴，该轴被一种疾病变异基因改变，并赋予宿主肺气肿的易感性。由Elsevier Inc.发表。

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.Published by Elsevier Inc.