Dysregulated tissue niche potentiates resident lymphocytes to suppress an interferon-sensitive stem cell reservoir in emphysema

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-02, Vol.56 (3), p.576-591.e10
• Main Authors: Wang, Chaoqun, Hyams, Benjamin, Allen, Nancy C., Cautivo, Kelly, Monahan, Kiara, Zhou, Minqi, Dahlgren, Madelene W., Lizama, Carlos O., Matthay, Michael, Wolters, Paul, Molofsky, Ari B., Peng, Tien
• Format: Article
• Language: English
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.01.032

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 IFN-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a novel stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.