Developmental immune network of airway lymphocytes and innate immune cells in patients with stable COPD.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and immune dysfunction. However, the molecular alterations and precise origins of immune cells in COPD airways remain poorly understood. Methods: Here, CD45+ immune cells in bronchoalveolar lavage fluid and peripheral blood mononuclear cells were collected from four COPD patients and four healthy smokers to provide a comprehensive single-cell transcriptomic atlas of immune cells in COPD airways. Results: Notably, CD8+ T cells exhibited increased exhaustion, reduced cytotoxicity, and decreased TCR diversity in COPD airways. Especially, we identified two distinct exhausted CD8+ T cell clusters (CD8Tex_PDCD1 and CD8Trm_LAG3) originating from different developmental trajectories. Regulatory T cells had a reduced proportion and regulatory capacity in COPD airways, while CD4+ tissue-resident memory T cells displayed excessive Th2 responses and diminished Th1 responses. Additionally, monocyte-derived alveolar macrophages (Macro_SPP1) underwent lipid metabolic reprogramming and exhibited a shift to an anti-inflammatory phenotype with reduced phagocytosis and protease-antiprotease imbalance in COPD airways. Furthermore, macrophages (particularly Macro_SPP1) showed increased interactions with T cells via SPP1 and GALECTIN signaling, likely contributing to T cell suppression in COPD airways. Conclusion: Together, these findings elucidate the dysregulated immune responses in COPD airways and provide a valuable resource for identifying potential therapeutic targets to restore immune homeostasis in COPD.