Activation of CD8¹ T Cells in Chronic Obstructive Pulmonary Disease Lung

Rationale: Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate disease has not been well characterized at the single-cell and molecular level. Objectives: To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution. Methods: We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD (n = 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction (n = 5), end-stage COPD (n = 2), control (n = 6), or donors (n = 4). We validated in an independent patient cohort (N = 929) and integrated with the Hhip^1/2 murine model of COPD. Measurements and Main Results: Mild-moderate COPD lungs have increased abundance of two CD8¹ T cell subpopulations: cytotoxic KLRG1¹TIGIT¹CX3CR1¹ TEMRA (T effector memory CD45RA¹) cells, and DNAM-1¹CCR5¹ T resident memory (T_RM) cells. These CD8¹ T cells interact with myeloid and alveolar type II cells via IFNG and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8¹KLRG1¹ TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8¹KLRG1¹ TEMRA cells are similar to CD8¹ T cells driving inflammation in an aging-related murine model of COPD. Conclusions: CD8¹ TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8¹ T cells may have therapeutic implications for preventing severe COPD.