Spatial transcriptomics reveals compartment-specific cytotoxic T cell crosstalk with AT2 and goblet cells in advanced COPD

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and structural remodelling across different anatomical structures of the lung, including airways, parenchyma, and pulmonary vessels. However, compartment specific changes in immune cell composition and their communications with underlying structural cells remains incompletely defined. Methods Our study sought to assess the spatially resolved cellular organization of healthy and advanced end-stage COPD lungs using 10X Visium spatial transcriptomics. Non-negative matrix factorization was applied to identify transcriptional programs within spatially distinct areas. Data was validated through an integrative multi-modal approach, including flow cytometry, multiplex immunofluorescence, open access GeoMx Nanostring spatial transcriptomics and scRNA-seq datasets, and proof of concept in vitro co-culture experiments. Results Spatial mapping of advanced COPD lungs revealed compartment-specific immune and tissue remodelling programs. In the COPD parenchyma, molecular and immune signatures delineated macrophage-rich, remodelling–stress, and humoral B cell immune niches. Airway niches shifted from club cell/innate immunity in controls to goblet cell/adaptive immunity in COPD. Notably cytotoxic T cells colocalised with alveolar type 2 cells within the parenchymal remodelling–stress niche and goblet cells in COPD airways; predicted ligand–receptor interactions implicated these T cells in parenchymal cytotoxic injury and mucus-associated airway remodelling. Conclusions Our findings delineate compartment-specific cellular microenvironments and interaction networks that may orchestrate tissue remodelling in COPD. This work advances our understanding of immune-driven pathogenesis and pinpoints the cytotoxic T-cell axis as a candidate for targeted therapeutic strategies.