The proposer is an accomplished investigator who has spent six years in the US and wishes to return to her home country. Over the years, the research of the proposer has focused on the MHC-I antigen-processing pathway in infected cells and dendritic cells (DC) and on CD8 T cell priming. The main objective of this proposal is to obtain funding to help the proposer to return to and reintegrate into her home country and to establish a research group there.
The research project: The induction of protective CD 8 T-cell responses against intracellular pathogens requires that DC internalise pathogen-derived proteins (antigens) and process these into small peptides. Such peptides, presented by MHC-I molecules on the DC surface, will activate antigen-specific CD8 T-cells to eliminate infected cells. So far, the cellular mechanisms involved in antigen uptake and processing for "cross-presentation" by uninfected DC remain poorly understood.
This project aims to identify proteins that play a role i n antigen cross-presentation. We will use a lentivirus-expressed small interfering (si)RNA library that targets 34.000 mouse genes to silence the expression of single genes in hematopoietic stem cells that will be differentiated into DC. These DC will be tested for their capacity to cross-present antigens and DC that lack cross-presenting activity will be sorted using multi-colour flow-cytometry. siRNAs expressed in the purified DC will be identified by micro-array analysis. The function of the so identified gene products will be analysed using transfectant cell lines that express siRNA constructs of interest.
We expect to identify different categories of proteins that are essential for antigen presentation on DC and, thereby, to unravel the MHC-I antigen-processing pathway that operates in DC to present ingested antigens. The elucidation of the cellular mechanisms involved in antigen cross-presentation may help the rational design of effective CD8 T-cell-inducing vaccines.
Fields of science
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