Endothelial cell senescence shapes T cell activity in late-stage of chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a leading cause of death with few effective therapies. While clinical staging distinguishes mild to very severe disease, recent molecular and single-cell studies have revealed that progression involves distinct reprogramming of cellular and immune pathways rather than a simple linear escalation of inflammation. Yet, most studies have analyzed COPD without stratifying by stage, obscuring mechanisms specific to disease severity. To address this, we investigated serum proteomic profiles from the UK Biobank and applied machine learning to identify stage-specific protein signatures across COPD progression. Integration with single-cell and bulk transcriptomic datasets revealed that in severe COPD, endothelial cells exhibit a senescent phenotype characterized by elevated interleukin-6 (IL6) expression. Endothelial-derived IL6 correlated with reduced type 1 helper T cell (Th1) abundance and impaired interferon-γ signaling, indicating suppression of Th1-mediated immunity. These findings position endothelial senescence–driven IL6 signaling as a key pathogenic mechanism and potential therapeutic target in late-stage COPD.