Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Chaoqun Wang; Ben Hyams; Nancy C Allen; Kelly Cautivo; Kiara Monahan; Minqi Zhou; Madelene W Dahlgren; Carlos O Lizama; Michael Matthay; Paul Wolters; Ari B Molofsky; Tien Peng

doi:10.1016/j.immuni.2023.01.032

Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Immunity. 2023 Mar 14;56(3):576-591.e10. doi: 10.1016/j.immuni.2023.01.032. Epub 2023 Feb 22.

Authors

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan 528400, China.
² Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ari.molofsky@ucsf.edu.
⁷ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: tien.peng@ucsf.edu.

Abstract

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.

Keywords: COPD; HHIP; adventitia; alveolar stem cell; emphysema; fibroblast; hedgehog; interferon gamma; respiratory viral infection; tissue-resident lymphocytes.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Emphysema*
Humans
Lung
Lymphocytes
Mice
Pulmonary Disease, Chronic Obstructive*
Pulmonary Emphysema* / genetics
Stem Cells

Abstract

Publication types

MeSH terms

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