Intracellular routing of exogenous antigen within dendritic cells during crosspresentation
Final Report Abstract
The processof cross-presentation is essential for mounting immune responses against viruses and tumors. It allows professional antigen presenting cells, in particular dendritic cells, to take up foreign material and present it in a processed form to T cells on MHC class I molecules, thus initiating immune responses. Detailed knowledge about the mechanism of cross-presentation plays therefore a major role in vaccine design. Despite its importance there are still many unknown steps in this process, such as the regulation of antigen trafficking inside dendritic cells. We wanted to address pathways of exogenous antigens during cross-presentation in human dendritic cells. The first obstacle was that human dendritic cells are difficult to manipulate and assay systems are not as well established as for mouse cells. After considerable effort we decided to switch to the mouse system for initial screens and planned a follow-up in the human system. The cloning of various regulators turned out to be time-consuming. When another group published a study covering most aspects of our work, it was time to focus on alternative projects. Dendritic cells can undergo a process of maturation, changing their phenotype and function. The common view is that matured dendritic cells only present antigens encountered prior/during onset of maturation. Although this is well established for MHC class II presentation, there is much less known about regulation of cross-presentation during maturation. We started to investigate the effects of different maturation stimuli on the ability of dendritic cells to cross-present. We found certain conditions that enhanced cross-presentation but also many that abrogated the process. Using the different stimuli as tool, we try to figure out the mechanism that allows or prevents antigens to be cross-presented. Simple parameters such as a decrease in antigen uptake or a difference in phenotype have already been excluded as reason for altered cross-presentation in our system.
