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^+/- murine model of COPD. Measurements and Main Results: Mild-moderate COPD lungs have increased abundance of two CD8⁺ T cell subpopulations: cytotoxic KLRG1⁺TIGIT⁺CX3CR1⁺ TEMRA (T effector memory CD45RA⁺) cells, and DNAM-1⁺CCR5⁺ T resident memory (T_RM) cells. These CD8⁺ T cells interact with myeloid and alveolar type II cells via IFNG and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8⁺KLRG1⁺ TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8⁺KLRG1⁺ TEMRA cells are similar to CD8⁺ T cells driving inflammation in an aging-related murine model of COPD. Conclusions: CD8⁺ TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8⁺ T cells may have therapeutic implications for preventing severe COPD.

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