Immunological memory is the basis of vaccination. This has been the subject of intense study, but the underlying cellular mechanisms regulating the generation and persistence of long-lived memory T cells (TM) remain largely undefined. Recently, it was shown that CD8+ T cell responses following bacterial infection could be manipulated by modulating cellular metabolism. Since then immunometabolism has emerged as one of the main frontiers in science, and my research is leading in this field. I recently demonstrated that the promotion of mitochondrial biogenesis (MB) and fatty acid oxidation (FAO) in CD8+ T cells during an immune response is crucial for their development into long-lived TM cells. An important regulator of MB and FAO is the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family, and my preliminary data suggest that PGC-1 has a role in TM development. My proposal focuses on the novel concept that cellular metabolism and MB regulate CD8+ TM cell development. Importantly, this concept offers possibilities for pharmacological manipulation of TM formation.My objectives are (1) to determine the role of PGC-1 in mitochondrial metabolism during CD8+ TM development and (2) to investigate whether agents that promote MB enhance vaccine efficacy. For objective 1 I will generate CD8+ TM cells in vitro, and determine whether PGC-1 deficient CD8+ T cells have a defect in functional TM cell formation due to impaired mitochondrial metabolism. In addition, I will determine whether PGC-1 deficient CD8+ T cells will form functional TM cells in vivo. For objective 2 I will test whether MB-inducing drugs can improve TM cell development and function, both in vitro and in vivo. My project will provide insight into the mechanism of MB and TM development, and can lead to the development of novel vaccine strategies that could apply to a variety of diseases.