The role of cell death induced in microbial infections for the development of the antimicrobial immune response

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The aim of this project is to understand the role of cell death that occurs during microbial infections for the development of a productive immune response. As we have shown earlier, ingestion of bacteria induces cell death in granulocytes and macrophages. Cell death can occur by either apoptosis or necrosis and leads to the efficient uptake of the dead cell by dendritic cells (DC), which in turn can present antigen contained in the dead cells to T cells. Viral infection was further shown to induce necrosis in infected cells, and necrosis was again sufficient for uptake of the dead cell by DC. From these observations we derive the hypothesis that cell death induced during microbial infections is an important way to make microbial antigen available to DC and consecutively to T cells. The investigation of this notion is the subject of this proposal, and will include exploration of the following questions: 1. What are the factors that determine the development of a productive immune response upon uptake of a dead cell? 2. How does the form of cell death (apoptosis or necrosis, with or without the participation of microbial agents) and microbe-dependent stimulation affect maturation of DC and their capacity for cross-presentation? 3. How do these factors contribute in vivo to determine the outcome of an adaptive immune response? These questions will be addressed in models of genetically modified mice and receptor-independent macrophage stimulation. Experimental systems will include in vitro and in vivo investigation of DC and T cell function.