Enhancing Pathogen-specific Memory CD8+ T cell Responses in Vivo

DESCRIPTION (provided by applicant): The design of better vaccines focuses on optimizing numbers, functional features and longevity of memory cells in vivo. Current research indicates that the achievement of such goals involves optimizing three distinct signals during vaccination, which are antigen presentation, co-stimulation and inflammation. The effective delivery of these signals during the priming of vaccine-induced immunity is usually associated with robust effector and memory lymphocyte responses, and the ability of memory T cells to efficiently re-expand upon secondary antigen encounter. In addition, maintenance of memory cells is dependent on homeostatic cytokines and expression of sufficient levels of the receptors for these cytokines. While unraveling the mechanisms of differentiation of T cells into potent memory cells is critical to improve vaccination strategies, an alternative possibility that has only been minimally explored is to develop methods to enhance the activation and expression of effector functions of vaccine-induced memory T cells at the time of infection. The success of such an approach requires a thorough understanding of how memory T cells undergo activation in vivo, which is a major goal of the current proposal. Over the past several years, we developed an experimental system to study the activation of memory CD8+ T cells in vivo in mice infected with the intracellular bacterium Listeria monocytogenes (Lm). With this system, we established that memory CD8+ T cells with the capacity to protect against lethal infection secreted the proinflammatory chemokine CCL3/MIP1 upon recognition of their cognate antigen, a feature that was lacking in memory cells from non-protected animals. CCL3 secretion by protective memory CD8+ T cells promoted efficient recruitment and activation of phagocytes, specifically neutrophils and a distinct subset of monocytes known as inflammatory monocytes, leading to microbial pathogens elimination. Most interestingly, our recent data show that the initial activation of memory CD8+ T cells in vivo is orchestrated by inflammatory monocytes and is independent of recognition of cognate antigen. Our working hypothesis postulates that inflammatory monocytes are central to optimal recall immune responses, both through activation of memory cells and for effective clearance of microbial pathogens. The current application proposes to investigate the molecular mechanisms that regulate memory CD8+ T cell activation in vivo and lead to enhanced pathogen killing. We will also assess such mechanism in models of inflammatory diseases such as type I diabetes. As specific aims for this proposal, we will establish (i) the contribution of cognate antigen recognition and inflammatory signals to memory CD8+ T cell activation in vivo, (ii) how inflammatory monocytes orchestrate the reactivation of memory CD8+ T cells and (iii) whether inflammatory monocytes contribute to memory CD8+ T cell-mediated autoimmunity. We anticipate the results of this work to lay the foundations for best design of future therapies modulating the reactivation of memory CD8+ T cells.