Lipid bodies organelles and the cross-presentation of cell-associated antigens by MHC class I in phagocytic dendritic cells

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Dendritic cells (DCs) are a specific cell type of the immune system. They act as sentinels able to warn T cells to get activated and to proliferate in case of danger. Once danger has gone, some T cell specific for the antigen keep on patrolling and they are termed as memory T cells. In case of antigen reencounter, they have the interesting ability to respond faster and better. Practically, this process of memorization is the basis of vaccination during which the immune system acquire the ability to respond faster and better to a given pathogen. We are studying the beginning of the process which is termed as "antigen cross-presentation to T cells". A specific population of DCs activates a family of T cells called CD8+ T cells that have the ability of kill antigen-bearing cells like cells infected by virus during viral infection, for instance. Antigen cross-presentation by DCs, in this case, takes place because DCs can eat (phagocytose) dead cells that carry antigens. After their meal, DCs digest dead cells and then sample antigens (peptide molecules) out of the dead cell body to present them on display molecules (called MHC class I) at their surface. CD8+ T cells see the association of peptides with MHC molecules at the surface of the DCs. The focus of our research is : what is happening during the digestion ? how the small antigen get extracted from the dead cell body that had been eaten by the DC ?We had already found an organelle dedicated to store fat (lipid bodies) that regulates antigen cross-presentation. We want to understand better how it work. This research grant intend to test the function of some genes that enable to enable cells to eat a little pieces of themselves to produce energy quickly in case of stress. This process is called autophagy and also target these lipid bodies. We wonder is autophagy may not regulate, perhaps through lipid bodies regulation, the digestion of dead cell bodies and the production of the peptide antigen-MHC class I complexes. To test this hypothesis, we are going to develop some mutant mice in which autophagy genes or some regulator of autophagy are inactivated into DCs. We will use these mice to analyse what autophagy is doing during the phagocytosis of dead cells and to determine if autophagy is important for the cross-presentation of antigens to CD8+ T cells.