Project 467112

Dysfunction of CD8+ T Cell Immunometabolism in Advanced Liver Fibrosis Hepatitis C virus (HCV) infection and non-alcoholic fatty liver disease (NALFD) place a significant burden on individuals and healthcare systems worldwide. Today, NAFLD is the primary source of chronic liver disease, and can be partially attributed to the rising trends in obesity, type 2 diabetes mellitus, and physical inactivity. Chronic liver insult in the form of viral infection or fatty diet result in the progressive accumulation of fibrosis, or scar tissue, in the liver. Fibrosis hinders liver function and has detrimental effects on CD8+ T cell immune response, while increasing the risk of end-stage liver disease and hepatocellular carcinoma. However, the mechanisms for such dysfunction are not well characterized. The study of immunometabolism, which is concerned with how immune cells acquire energy, will help elucidate the mechanisms responsible for CD8+ T cell dysfunction in chronic liver disease. I hypothesize that features of immunometabolism underlie lasting CD8+ T cell dysfunction in hepatotoxin and diet-induced liver fibrosis. Liver fibrosis characteristic of HCV infection and NAFLD will be reproduced in animal models. Mice will be injected with carbon tetrachloride, a potent inducer of liver damage, or fed a high-fat choline deficient, methionine deficient diet. This project aims to determine if CD8+ T cell dysfunction is associated with cell survival and metabolism through high-throughput flow cytometry analysis of CD8+ T cell function and survival. Metabolic features will also be evaluated by quantifying the extracellular acidification rate and oxygen consumption rate, indicators of glycolysis and oxidative phosphorylation respectively.