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Identification of cellular proteins involved in uptake and cross-presentation of pathogen-derived proteins by professional antigen presenting cells

Final Activity Report Summary - AG-PROCESSING BY DC (Identification of cellular proteins involved in uptake and cross-presentation of pathogen-derived proteins by ... antigen presenting cells)

The main aim of this grant was the reintegration of the recipient, who had made her career in science mainly outside the European Union, into her country of origin. Immediately prior to the start of this grant, the recipient moved to the University of Utrecht in the Netherlands, to (re-) establish a research group there. Focus of research since then has been the elucidation of pathways via which pathogen-derived proteins are processed by the host, in order to mount a protective immune response. Dendritic cells, which are professional antigen presenting cells, are known to play an essential role in this process. In specific, DC phagocytose pathogen-derived proteins and display these in the context of MHC class I on their cell surface. In this way, they can interact with naive pathogen-specific CD8 T cells that then become activated, leading to clearance of the infecting agent.

One still unelucidated step in the processing of such phagocytosed antigens remains the route by which the antigens enter the class I antigen processing pathway, which usually starts in the cytosol (nucleus). In order to unravel this pathway in further detail, we performed a functional genomic screen. A siRNA library was introduced into bone marrow-derived stem cells, that were then differentiated into DC, and the ability of these DC to present a model antigen was analyzed. Our asays showed that DC, belonging to one specific subset that is known to croos-present phagocytosed antigens, actually consisted of again different subsets with very different capabilities to cross-present. Our future experiments aim to further define these subsets, and the early events following antigen uptake that protect antigens from degradation in the phagosome and allow them to enter the cytosol.

During the project period, the recipient applied for and acquired several grants from different funding agencies. Her group presently consists of several PhD students, a post doc and a technician and focuses on antigen processing and T cell responses to infectious agents.