Single‐Cell RNA Sequencing of Human Lung Tissues Reveals Metallothionein‐Positive T Cells as a Novel Potential Marker of Susceptibility to Chronic Obstructive Pulmonary Disease

ABSTRACT Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease with complex pathogenesis. Identifying high‐risk populations and implementing timely prevention strategies are critical to reducing the disease burden. Single‐cell RNA sequencing of lung tissue from control never‐smokers, patients with pre‐COPD, and COPD patients revealed a novel T cell subset characterized by high expression of metallothionein (MT) genes, designated MT‐high T cells. These cells were progressively depleted in the lungs with disease progression. A similar decline was observed in the peripheral blood using flow cytometry, highlighting the potential of these cells to serve as an accessible biomarker of disease progression. Functional analysis indicated that MT‐high T cells suppress CD8 + T cell cytotoxic activity, suggesting a key immunoregulatory role in disease pathogenesis. Receiver operating characteristic curve analysis demonstrated the excellent potential of MT‐high T cell frequency to predict susceptibility to COPD. These findings establish MT‐high T cells as promising biomarkers for identifying individuals at risk for COPD and as novel targets for future therapeutic and prophylactic strategies.