Abstract
Exosomes are a particular type of extracellular vesicle, characterized by their endosomal origin as intraluminal vesicles present in large endosomes with a multivesicular structure. After these endosomes fuse with the plasma membrane, exosomes are secreted into the extracellular space. The ability of exosomes to carry and selectively deliver bioactive molecules (e.g., lipids, proteins, and nucleic acids) confers on them the capacity to modulate the activity of receptor cells, even if these cells are located in distant tissues or organs. Since exosomal cargo depends on cell type, a detailed understanding of the mechanisms that regulate the biochemical composition of exosomes is fundamental to a comprehensive view of exosome function. Here, we review the latest advances concerning exosome function and biogenesis in T cells, with particular focus on the mechanism of protein sorting at multivesicular endosomes. Exosomes secreted by specific T-cell subsets can modulate the activity of immune cells, including other T-cell subsets. Ceramide, tetraspanins and MAL have been revealed to be important in exosome biogenesis by T cells. These molecules, therefore, constitute potential molecular targets for artificially modulating exosome production and, hence, the immune response for therapeutic purposes.
Highlights
Exosomes are nano-sized membranous vesicles (40–100 nm in diameter) that are secreted into the extracellular space by many cell types
Consistent with the presence in exosomes of endosomal sorting complexes required for transport (ESCRT)-associated machinery, tetraspanins and condensed membranes, it has been proposed that distinct molecular mechanisms sort the exosome cargo and deform the membranes required for the inward invagination of intraluminal vesicles (ILV) destined for secretion as exosomes (Figure 1)
The incorporation of the B-cell receptor into condensed membranes, a key step to ensure the sustainment and the amplification of B-cell receptor-mediated signaling, depends on the expression of CD81 (Cherukuri et al, 2004); in T cells the tetraspanin CD82 mediates the association of the actin cytoskeleton with compact membranes, which is necessary for triggering T-cell receptor-dependent signaling (Delaguillaumie et al, 2004); the incorporation of CD9 into condensed membranes domains is crucial for the cell fusion during osteoclastogenesis (Ishii et al, 2006); and the recruitment of CD63 to filopodia tips during the adhesion of platelets depends on the membrane compaction (Heijnen et al, 2003)
Summary
Exosomes are nano-sized membranous vesicles (40–100 nm in diameter) that are secreted into the extracellular space by many cell types. The accumulation of “membrane-bound vesicles” in the lumen of MVE as result of the inward invagination of its limiting membrane, as well as the release of “vesicular inclusions” into the extracellular space after the fusion of MVE with the plasma membrane was firstly observed by Philip Stahl’s group in 1983 during studies of the traffic of the transferrin receptor in rat reticulocytes (Harding et al, 1983) This finding was consistent with the selective externalization of this receptor in vesicles by maturating sheep reticulocytes observed simultaneously by Rose Johnstone’s group (Pan and Johnstone, 1983). A few years later, the term exosomes was coined to refer to the population of vesicles that are released into the extracellular space upon fusion of MVE with the plasma membrane and that can be recovered from the 100,000 × g pellet of cell-free supernatants of cell culture medium or extracellular fluids (Johnstone et al, 1987)
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