| Phagocytosis is a mechanism that certains cells have acquired during evolution to internalize large particles like mineral fragments, apoptotic bodies and pathogens so they can be killed and degraded. Cells that are routinely using phagocytosis are named professional phagocytes and form the first line of defence in innate immunity. In mammalians, professional phagocytes are composed of three cellular types, the macrophages, the dendritic cells and the neutrophils. The particles internalized by professional phagocytes are found in an organelle named phagosome, which interacts with the organelles from the endocytic pathway, the endosomes and lysosomes, so it can gradually acquire the elements that will allow it to perform its cellular functions. These functions include microbicity against phagocytosed pathogens caused by the synthesis of reactive oxigen species and protein degradation by proteases. Another function of the phagosome is to process exogenous peptides from pathogen degradation on molecules of the class II major histocompatibility complex (MHC), which are then transported to the phagocyte surface so they can stimulate CD4+ T-lymphocytes and promote the adaptive immune response against the phagocytosed pathogens.; The objective of the work described here was to use proteomics to characterize in macrophage the phagosome proteome and discover new functions linked to this organelle. In the results reported here, we describe the molecular events implicated in crosspresentation, which allow the phagosome to process exogenous peptides on MHC class I molecules so that CD8+ cytotoxic T-lymphocytes can be stimulated. The cytotoxic T-lymphocytes play an important role in the control of infections by recognizing infected cells of the host and eliminating them. In this new model of exogenous antigen cross-presentation that we describe here, the phagosome is self-sufficient for all the steps of cross-presentation. We have thus divided cross-presentation in five steps: (1) retrotranslocation of exogenous antigens from the phagosome lumen to the cytosol, (2) ubiquitination of exogenous antigens in the cytosol, (3) degradation by the proteasome recruited to phagosome of exogenous antigens in the cytosol, (4) retranslocation inside the phagosome of generated exogenous peptides and (5) loading within the phagosome of exogenous peptides on MHC class I, and transport of the peptide:MHC class I complex to the surface. In the second part of the work presented here, we describe how interferon-gamma, a cytokine playing an important role in the stimulation of cells of the immune system, modifies the protein composition of the phagosome to make it more efficient in its various functions. Among the functions stimulated by interferon-gamma in the phagosome, we note the increase of microbicity against pathogens, of protein degradation, of interactions with endosomes and of antigen presentation. |
