Project Summary Chronic liver diseases are a collection of disorders that result in significant morbidity and mortality worldwide. The overwhelming burden of these diseases results in the liver being the second most transplanted organ. As a result of a dramatic rise in the incidence of obesity and alcohol consumption, the rate of liver transplantation continues to climb world-wide. Despite the significant impact of chronic liver disease on society, there are no effective therapies to ameliorate disease outside of lifestyle modification and liver transplantation. Thus, a more rigorous understanding of the mechanisms that drive the progression of chronic liver disease is required to identify novel targets for therapeutic intervention. Our previous publication demonstrated a significant accumulation of T lymphocytes in the liver of individuals with Non-Alcoholic Steatohepatitis (NASH)-induced cirrhosis. However, the precise role of T cells in the progression of NASH has yet to be firmly established. The preliminary studies presented in this application have identified a yet to be appreciated role for T cell activation and clonal expansion during NASH. In this application we demonstrate that T cell clonal expansion is a common event in both humans with NASH-induced cirrhosis and mice with NASH. These are the first studies to identify T cell clonal expansions in the liver of humans and/or mice with NASH and link T cell activation and function with NASH pathology. However, the exact antigenic cause of T cell activation or if these T cells are inducing or suppressing disease progression is unknown. The studies in this application aim to answer these two fundamental questions by defining (1) the timing of T cell clonal expansion in the liver during the progression of NASH, (2) the antigens recognized by clonally expanded T cells, (3) the antigen presenting cell (APC) that drives T cell clonal expansion, and (4) if eliminating T cell clonal expansion through depletion of clonally expanded T cells or the APCs presenting antigens to these T cells results in prevention and/or resolution of disease. Completion of these studies will provide a paradigm shift in our understanding of the pathogenesis of NASH and will generate the tools necessary to define the role of T cells in the progression of other chronic liver diseases.