Principal Investigators
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Benjamin Medoff, MD, Principal Investigator, Massachusetts General Hospital | Jacques Deguine, PhD, co- Investigator, The Broad Institute | Jay Rajagopal, MD, co-Investigator, Harvard University |
Research Description
Mapping Airway Epithelial and Immune Cell Interactions in Lung Health and Disease
Our project within LungMAP3 focuses on a comprehensive analysis of cellular communication within the airways in health and in asthma and chronic obstructive pulmonary disease (COPD). These diseases, which together account for the highest global burden of disability and mortality from chronic respiratory diseases, are characterized by altered interactions between airway epithelial cells (AECs) and immune cells, leading to chronic inflammation and structural remodeling of the airways, which progressively disrupts normal lung function.
We hypothesize that unique AEC-immune circuits, involving both common and rare AEC subtypes, as well as specialized structures like hillock islands and inducible bronchus-associated lymphoid tissue (iBALT), are central to driving the chronic inflammation seen in asthma and COPD. These structures appear to foster resident memory T cells and B cells, perpetuating local immune responses that shape the clinical trajectory of each disease. Our overarching goal is to construct a highly detailed, spatially resolved atlas of these interactions, which could pinpoint precise therapeutic targets for modulating disease-specific pathways in asthma and COPD.
Using airway samples from research bronchoscopies, lung resections, and explant tissue, we will employ single-cell RNA sequencing and high-resolution spatial transcriptomics to define the spatial arrangements and interactions between immune-responsive AECs and immune cells in three patient cohorts: asthma, COPD, and healthy controls. Further, using a 3D organoid system, we will also functionally validate these interactions by disrupting specific signaling pathways with CRISPR modifications, thereby isolating disease-relevant phenotypes associated with AEC-immune cell communication in asthma and COPD.
To capture the adaptive immune response in each condition, we will analyze airway brushings for T and B cell receptor diversity using single-cell TCR and BCR sequencing. Spatial mapping of these receptors in resections and explant tissue will allow us to identify and localize disease-driving immune clones that expand within affected tissues. This approach is expected to reveal disease-relevant specificities of T and B cell populations in each disease, uncovering distinct or shared immune responses that could inform targeted therapeutic strategies.
Through this research, we aim to delineate the distinct and overlapping cellular communication networks that contribute to chronic inflammation in asthma and COPD, which could lead to new precision therapies. Our findings will support the creation of a detailed cell-specific atlas of the airway immune microenvironment in health and disease, making valuable contributions to LungMAP3.


