Chronic Obstructive Pulmonary Disease (COPD) is now the 3rd leading cause of death in the United States, and the only cause of death that is on the rise. Smoking is the most common risk factor for COPD, however there are other environmental triggers such as dust, smoke, sand, or aerosols. Nearly one in ten VA patients are diagnosed with COPD and the costs associated with these patients are ten times higher than for all other conditions. Despite the prevalence of COPD, our understanding of the immune mechanisms that drive development of the disease is incomplete. There is increasing evidence that cytotoxic CD8+ T cells are critical to the pathology of COPD. Work done by the PI and collaborators has identified mucosal associated invariant T (MAIT) cells as an ‘innate’-like lung-resident CD8+ T cell population capable of recognizing airway epithelial cells infected with COPD-associated lung pathogens. Although lower airway bacterial infections are associated with COPD and are correlated with airway function, the mechanisms by which infections develop and contribute to COPD pathogenesis is not yet clear. Because CD8+ T cells recognize and destroy target cells infected with pathogens, lung-resident CD8+ T cells like MAIT cells may be important for containment of bacterial infections. In fact, we find that MAIT cells, which are highly enriched in human airways, have reduced frequency in the peripheral blood of COPD patients. Furthermore, we find that MAIT cells, while capable of controlling the growth of bacteria, are impaired in their ability to make IFN-g in response to bacterially infected airway epithelial cells from patients with COPD. The effect of COPD on MAIT cell function is not known and may be essential to understanding how lower respiratory infections contribute to the development of COPD and COPD exacerbations. This proposal is focused on determining the mechanisms by which COPD alters the frequency and function of MAIT cells, particularly with regard to recognition of bacterially infected airway epithelial cells. Additionally, we will determine the consequences of altered MAIT cell activation on bacterial survival and inflammation. This project contains two Aims: Aim 1. Define the frequency and functional capacity of MAIT cells among CD8+ T cells from COPD lungs. Aim 2. Define the mechanisms underlying MAIT cell-mediated killing of bacteria, and how these mechanisms are modulated in COPD.