Despite decades of research, no effective therapies exist to circumvent the irreversible alterations in lung function associated with COPD. Further, complications of COPD arise from acute and chronic exacerbations that amplify ongoing injury and remodeling that increase morbidity and mortality. The pathophysiology of exacerbations is poorly understood, but is primarily due to inflammation from infections. Some patients are more susceptible to exacerbations and represent an `exacerbator phenotype' associated with COPD-dependent changes in innate and adaptive immunity. Natural killer (NK) cells are a heterogeneous population of lymphocytes that are important in the defense against infections. They are also involved in initiating and directing active immune responses through cytokine production. NK cells recognize pathogen-infected cells expressing ligands for an array of activating and inhibitory receptors. Research by our lab and others identified multiple effects of smoking on NK cell function that suggest these changes are significant in the pathophysiology of COPD exacerbations. Traditionally, NK cells were divided into immature and mature subpopulations based on CD16 and CD56 expression. Recently, high-dimensional analysis of NK cells revealed a surprisingly high degree of phenotypic diversity and that each individual has thousands of unique populations of NK cells. Although the expression of various NK cell surface markers provides clues about the function of subpopulations, the significance of each populations is unknown. Therefore, we probed NK cell phenotypes from a cohort of non-smokers, smokers, and COPD patients targeting NK cell activating and inhibitory receptors. These studies revealed several unique NK cell populations that differed between groups. Further analyses showed that the size of NK cell subsets associated with a previous exacerbation with 95% confidence. Based on these findings, we hypothesized that smoking alters NK cell heterogeneity which leads to the emergence of unique populations that can serve as biomarkers of increased risk of COPD exacerbations. We will test this hypothesis with the following Specific Aims: Aim 1: Define the natural history of NK cell diversity and plasticity in never smokers and smokers. Previous analyses of NK cell populations over time are based on limited phenotyping and high-dimensional analyses of NK cell populations have been derived from a single time point. To advance our understanding of the heterogeneity of NK cell populations over time, we will conduct a 3-year prospective longitudinal analysis of NK cell plasticity in never smokers and current smokers without COPD. Aim 2. Define whether alterations in NK cell populations precede or occur following exacerbations in COPD to determine the usefulness of NK cell phenotyping as a biomarker of future exacerbations. Preliminary data identify alterations in NK cell subsets associated with COPD exacerbations. However, we do not know if these al...