Natural Killer T (NKT) cells are unconventional T cells which recognize lipid antigens presented by the atypical MHC class I molecule CD1d. While NKT cells are abundant in the human and murine liver and play important roles in liver diseases such as autoimmune hepatitis and primary biliary cirrhosis, little is know about their regulation. The microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum-resident protein which catalyzes lipid transfer onto Apolipoprotein B and assists in the assembly of chylomicrons and very low density lipoproteins. In addition, MTP can transfer phospholipids onto CD1d and regulate CD1d antigen presentation and NKT cell activation thus establishing a link between metabolism and immune function.Here, I propose to investigate the regulation of hepatic CD1d-restricted lipid antigen presentation by MTP and its role in NKT cell activation and homeostasis in the liver. Using two unique mouse models that allow for tissue-specific deletion of MTP in hepatocytes and tracking of NKT cells via green fluorescent protein, I will study the regulation of CD1d biosynthesis, stability, and antigen presentation by hepatocyte MTP. In addition, I propose to investigate NKT cell activation and homeostasis in mice with hepatocyte-specific MTP deletion.These studies will provide, for the first time, insight into the regulation of lipid antigen presentation by hepatocytes and will provide the basis for therapeutic targeting of MTP and CD1d in NKT cell-mediated liver diseases. In addition, these studies will significantly extend our knowledge about the mechanisms of cross-regulation of metabolic and immune pathways.The Marie Curie International Reintegration Grant will provide essential funding for this project and will ensure my successful scientific reintegration thereby supporting scientific excellence in Europe.