Mechanisms of T-Cell Memory and Protective Immunity to Intracellular Pathogens Establishment and maintenance of protective memory B and T cells is fundamental to the development of effective vaccines. To date, protection afforded by the most effective vaccines depend upon the elicitation of neutralizing antibodies. However, protection against diseases such as Tuberculosis, Malaria and HIV would also require memory CD8 T cells. The overarching goal of our research therefore, is to understand the cellular and molecular basis of T cell memory to systemic and mucosal infections. In an immune response, naïve T cells differentiate into effector cells and a fraction of effector cells further differentiate into long-lived memory T cells. We are interested in identifying the signaling pathways and transcriptional mechanisms that regulate the differentiation and long-term persistence of systemic and tissue resident memory T cells. First, we are elucidating the metabolic and transcriptional basis for the programming of durable CD8 T-cell memory by the PI3K/AKT and NF-KB signaling pathways. Mechanistic information from these studies will pave the path for developing vaccination strategies to modulate signaling pathways in order to engender durable and protective CD8 T cell memory. Second, it is becoming increasingly clear that the combination and nature of innate immune signals play a vital role in programming protective T-cell memory. We are currently exploring the use of combination adjuvants that engage multiple innate immune pathways and engender potent and durable systemic and mucosal T-cell memory to non-replicating antigens.