The adaptive branch of the immune system consists of B and T lymphocytes. CD8 T cells are key players in mediating immunity to intracellular pathogens and tumors. CD8 T cells that encounter antigen in the context of MHC class I become activated and initiate a program of proliferation and differentiation into effector cytotoxic T lymphocytes (CTL). Typically, in response to an acute viral infection, a naive CD8 T cell may go through more than 15 divisions in 6 days to generate thousands of effector progeny. At the peak of this response, also called the primary response, antigen has typically been cleared and in the following days more than 90% of the effector CD8 T cells die. This process called contraction leaves behind a surviving fraction of T cells that persists as long-lived memory cells. Apart from their longevity, memory cells are further characterized by their ability to respond with enhanced efficacy to rechallenge with the same antigen (secondary response). These features, plus their increased numbers, allow memory CD8+ T cell to provide efficient long lasting immunity against previously encountered pathogens. While many established vaccination programs are mainly dependent on an efficient antibody response, current challenges such as malaria, HIV and tuberculosis appear to require a different approach. CD8 T cells are a key player protecting us against intracellular pathogens (such as viruses or certain intracellular bacteria). A thorough understanding of how CD8 T cell memory is generated and maintained will provide us with more insight and better vaccination strategies. We want to focus our research on the poorly understood contraction part of the CD8 T cell response. The broad goal of my research is to understand how the transition of CD8 T cells from the effector to the memory stage is regulated. The more specific goal for the next 3 years is to shed light on the mechanisms that control certain aspects of the contraction phase and the ensuing memory phase of the CD8 T cell response. RELEVANCE: The proposed research will help us understand better how the immune system responds to infection. This will aid in developing and improving vaccination strategies.