DESCRIPTION (provided by applicant): Mortality from chronic infectious diseases, including Hepatitis C, HIV, and tuberculosis, remains a major problem among Veterans, making the development of new vaccines an important priority of biomedical research. Immunologic memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Traditional vaccination strategies are very effective at generating neutralizing antibodies against bacteria and viruses. However, a vaccine capable of generating robust T cell memory is still beyond our research, due, in part, to an incomplete understanding of the molecular basis for memory lymphocyte fate specification. Moreover, the molecular mechanisms underlying immune `exhaustion,' a state in which T cells are rendered ineffective during many chronic viral infections, remain incompletely understood. Thus, a fundamental understanding of how memory lymphocyte fate is specified, as well as what goes awry in the exhausted state, is a crucial first step in rational vaccine design for infectious diseases such as HIV, HCV, malaria, and tuberculosis. Our underlying hypothesis is that previously unappreciated molecular determinants control the specification of terminal effector and memory (TCM, TEM, and TRM) cell fates as well as the exhausted CD8+ T cell state. Our goal is to identify and validate these determinants using innovative multi-disciplinary approaches that include single-cell RNA sequencing, computational analyses, and immunological techniques.