Activation of CD8+ T Cells in Chronic Obstructive Pulmonary Disease Lung

Abstract

<b>Rationale:</b> 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. <b>Objectives:</b> To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution. <b>Methods:</b> We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD (<i>n</i> = 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction (<i>n</i> = 5), end-stage COPD (<i>n</i> = 2), control (<i>n</i> = 6), or donors (<i>n</i> = 4). We validated in an independent patient cohort (<i>N</i> = 929) and integrated with the <i>Hhip</i>^+/- murine model of COPD. <b>Measurements and Main Results:</b> 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 <i>IFNG</i> 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. <b>Conclusions:</b> 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.