Dendritic cells offer tremendous potential in clinical applications where modulating immune responses are desired. Thanks to their potent ability to stimulate T cell responses, DC are under intense investigation as vaccines for a variety of diseases, and have shown particular promise in the cancer arena. DC are a diverse group of cells with distinct phenotypes, and functions representative of their unique subset and lineage. GM-CSF has been used successfully for years to generate large numbers of DC for study in vitro and is still the predominant cytokine used to generated DC for vaccines. DC that are developed and differentiated through GM-CSF activity are thought to represent a distinct myeloid lineage and the immediate precursors of DCs are monocytes. Upon infection with a variety of pathogens including Listeria monocytogenes, a surge in GM-CSF is observed in the serum of infected animals. However, the function of myeloid progenitor cell types in the infectious disease process remains incompletely defined. Therefore with this proposal we will test the hypothesis that infection of poorly developed myeloid cells (common myeloid progenitors and monocyte/dendritic cell progenitors) with Listeria will inhibit the overall immune response by imparting immunosuppressive function and enhancing the growth and spread of bacteria. To test this hypothesis we propose two specific aims: 1) To determine how infection of myeloid cells at distinct stages of development affects their function as antigen presenting cells. And 2) To determine how the developmental status of myeloid cells affects the fate of Listeria within the cell.
Thanks to their ability to stimulate strong immune responses, dendritic cells (DC) hold great promise as potential vaccines for a variety of diseases and cancer. This project is aimed at enhancing our understanding the ontogeny of DC function toward optimizing the design of such vaccines.