ABSTRACT Chronic obstructive pulmonary disease (COPD) is a highly prevalent disorder that is primarily attributed to smoking, and which disproportionately affects Veterans. New therapeutic approaches are needed as neither current therapies nor smoking cessation halt the irreversible decline in lung function once initiated. The chronic infiltration of inflammatory cells is a hallmark of COPD and results from both innate and adaptive immune responses. Natural killer cells (NKs) are innate cells that have been shown to mediate rapid cytotoxicity towards autologous lung epithelial cells in COPD. Our long-term goal is to understand whether we can use an immunotherapy approach to suppress lung NK cytotoxicity against lung parenchyma without compromising immune surveillance. To this end, regulatory T cells (Tregs) have been shown to suppress NKs but Tregs are known to be decreased in COPD, suggesting that the loss of Tregs may be contributing to the increased cytotoxicity of lung NKs in COPD. Our Central Hypothesis is that increasing Treg functionality will block the cytotoxicity of lung NKs from COPD patients and will reduce NK-driven lung destruction in a murine model of COPD. Our proposal will use human lung tissue and paired peripheral blood and an established murine model of cigarette smoke exposure. Aim 1 will confirm the ability of circulating human Tregs to suppress lung NK cytotoxicity in vitro and will determine whether this is limited to a specific Treg subset. After confirming the potential for Tregs to modulate NKs, we will focus on addressing critical knowledge gaps essential to designing trials of novel Treg therapies in COPD. The goal of Aim 2 will be to test the in vivo effects of adoptively transferring Treg subsets into our murine model. Specifically, we will evaluate Treg suppression of NKs and T cells and also determine how the inflammatory environment effects Treg phenotype, stability, and migration. In Aim 3, we will focus on improving the stability of Tregs as they have been shown to have functional plasticity when introduced to a proinflammatory environment. Increasing the stability of the Tregs should also increase their long-term suppressive potential. We will conclude by testing the effects of our optimized Treg therapy in a 6-month cigarette smoke exposure murine model and determine whether we can halt progressive lung destruction. Successful completion of this project will provide crucial data, which are not currently available, on the potential of Treg therapy to regulate NK cytotoxicity and treat COPD. There are currently >280 ongoing clinical trials using Treg therapy for the treatment of autoimmune disease and organ transplant, but there are no studies of Treg therapy in COPD.