Molecular machinery involved in cross-presentation of cell-associated antigens
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Dendritic cells (DCs) play an important role in initiation of cytotoxic T cell (CTL)-mediated immune responses against pathogens and tumours. In order to prime the relevant T cells, DCs acquire antigens from infected or cancer cells and process them for presentation on the MHC class I molecules. Despite over forty years of research since this process (referred to as cross-presentation) has been described, it is still poorly understood on the molecular level. One of the roadblocks is that we are missing many of the key players involved.
The aim of this project is to identify and characterise new proteins involved in the different steps of cross-presentation of cell-associated antigens. The overall goal is to understand in molecular detail how these proteins act in concert to control antigen acquisition, trafficking, and processing (for example, antigen export from endosomes into the cytosol, where proteasome can generate short peptides capable of binding to MHC class I).
The project will employ several cell biology, immunology, and genetic (including CRISPR-Cas9 genome engineering) techniques and will provide an opportunity to learn and develop novel microscopy, and flow cytometry-based assays.
Parnas, O., Jovanovic, M., Eisenhaure, T. M., Herbst, R. H., Dixit, A., Ye, C. J., Przybylski, D., Platt, R. J., Tirosh, I., Sanjana, N. E., Shalem, O., Satija, R., Raychowdhury, R., Mertins, P., Carr, S. A., Zhang, F., Hacohen, N. and Regev, A. (2015)
A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks.
Cell 162, 675–686 .
Joffre, O.P., Segura, E., Savina, A. and Amigorena, S. (2012)
Cross-presentation by dendritic cells.
Nat Rev Immunol. 12:557–569. doi:10.1038/nri3254.
Gutiérrez-Martínez, E., Planès, R., Anselmi, G., Reynolds, M., Menezes, S., Adiko, A.C., Saveanu, L., and Guermonprez, P. (2015)
Cross-Presentation of Cell-Associated Antigens by MHC Class I in Dendritic Cell Subsets.
Front Immunol. 6. doi:10.3389/fimmu.2015.00363.