Integrative phagosomal biology: antigen presentation and developmental programs in dendritic cells Dendritic cells phagocytose incoming pathogens and dead cells in peripheral tissues, and then migrate to the draining lymph nodes where they deliver to lymphocytes all the information required for the initiation of adaptive immune responses. This information relates to the nature of the pathogen, which is sensed, both directly through pattern recognition receptors (including Toll-like receptors, TLRs), and indirectly through different receptors for cytokines and stress factors. This information also concerns the structure of the antigens, which will be presented to T lymphocytes in the form of proteolytic peptides loaded on MHC molecules. Phagosomes play a critical role in the processing of antigens for presentation to both MHC class II-restricted CD4+ T cells, and to MHC class I-restricted CD8+ T cells (a process called cross presentation). Importantly, antigen processing and presentation to T cells is influenced by the environment of the dendritic cells and by the type of TLR-ligands engaged. The present project aims to identify the molecular basis for the regulation of phagosomal functions (including oxidation, pH control and degradation) and antigen processing during the different developmental programs of DCs. Our main specific aims are: 1) to analyse the regulation of the phagosomal function during dendritic cell maturation, 2) to identify novel molecular players and pathways in antigen cross presentation using shRNA- based screens, and 3) to image dynamically phagocytic dendritic cell functions, in vitro and in vivo. This project will provide an integrated vision of the phagosomal function of dendritic cells and of its regulation during dendritic cell maturation. It will unravel novel molecular players and pathways involved in the control of the phagocytic function in general, and will contribute to understanding the molecular basis of immune recognition.
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