The long-term objectives of this application are to enhance our understanding of the mechanisms responsible for the maintenance of functional and stable CDS* memory. Therefore, these studies will contribute to the rational design of better vaccine strategies to deal with current infectious disease threats. In this effort, we have recently uncovered a novel role for interleukin-2 (IL-2) in the generation of robust secondary, but not primary, CDS* T cell responses to acute infection. The experiments proposed herein will explore the precise mechanisms whereby IL-2 promotes the maintenance of functional CD8+ memory. Specifically, we will address three main questions. First, when does IL-2 signaling to CDS* T cells promote CDS* recall responses? We suggest three main possibilities: 1) IL-2 "programs" the development of functional CDS* memory during the primary response; 2) IL-2 maintains the ability of long-lived memory cells to respond to secondary encounter with antigen; or, 3) IL-2 directly promotes secondary expansion of CDS* T cells following rechallenge. To address this question, we will develop a system in which IL-2Ra expression can be inducibly inhibited at various phases of the immune response. Second, does IL-2 represent a form of [unreadable] CD4* T cell "help" in the maintenance of CDS* memory T cell function? To test this hypothesis, we will [unreadable] analyze immune responses to acute infection in a setting in which only CD4* T cells are deficient in their ability to make IL-2. Lastly, what are the mechanisms by which IL-2 enhances the responsiveness of CDS* memory T cells? Our previous research has suggested that reducing the number of CD4*CD25* regulatory T cells (TR) in the periphery can rescue recall responses by IL-2Ra-deficient CDS* T cells. By creating a setting in which TR can be specifically depleted in vivo while leaving other cell populations untouched, we will test the hypothesis that IL-2 opposes TR-mediated suppression of CDS* recall responses. In order to design better vaccines to deal with global health threats such as HIV, malaria and tuberculosis, we need a better understanding of the way our immune system generates and maintains protective immunological memory. In this endeavor, we will explore the role of the growth factor interleukin-2 in enhancing the ability of memory cells to respond to a second encounter with a pathogen. [unreadable] [unreadable] [unreadable] [unreadable]