2014 March ; 14(3): 195–208. doi:10.1038/nri3622. | Paul D. Robbins and Adrian E. Morelli
Extracellular vesicles (EVs), including exosomes, are small membrane vesicles derived from multivesicular bodies or the plasma membrane. They contain proteins, lipids, and nucleic acids that are transferred between cells, playing crucial roles in intercellular communication. EVs are involved in various physiological processes and have significant roles in immune regulation, both in non-immune and immune cells. This review focuses on the role of EVs in modulating immune responses and their therapeutic applications.
**Biogenesis and Traffic of Exosomes:**
Exosomes are generated by inward budding of the endosomal membrane, leading to the formation of intraluminal vesicles (ILVs) inside endosomes. These ILVs are then released as exosomes through the secretory or lysosomal pathways. The generation of exosomes involves the sorting of proteins and lipids into the endosomal membrane, delivery of cargo into ILVs, and excision of ILVs. Monoubiquitination of transmembrane proteins directs them to ILVs, which are then captured by the endosomal sorting complex for transport (ESCRT) machinery. Exosome biogenesis can occur through alternative mechanisms, such as sphingolipid-containing lipid rafts in the MVB membrane.
**Extracellular Vesicles in Antigen Presentation:**
EVs can directly or indirectly present antigens to T cells. Direct antigen presentation occurs when EVs carry MHC Class-I and Class-II molecules, which can stimulate CD8 and CD4 T cells, respectively. Indirect antigen presentation involves the transfer of p-MHC complexes to antigen-presenting cells (APCs) through exosome-mediated mechanisms. This can be facilitated by the interaction of EVs with DCs, which enhance the T-cell stimulatory activity of exosomes.
**Pathogenic and Native Antigens:**
EVs can transfer pathogenic antigens to APCs, promoting tumor-specific immune responses. For example, tumor-derived EVs containing native tumor antigens can be taken up by DCs and processed for cross-presentation to tumor-specific CTLs. Additionally, EVs can carry native antigens, such as those from viruses or bacteria, which can be presented to T cells.
**RNA Transfer:**
EVs also serve as carriers of genetic information, including mRNAs and small non-coding RNAs (ncRNAs). The transfer of RNAs from EVs to target cells involves docking and fusion of the vesicle membranes. This mechanism allows for the horizontal propagation of post-transcriptional regulation among APCs and other cell types.
**Activation and Immunosuppression:**
EVs can activate immune responses by promoting the maturation of DCs and macrophages, as well as by delivering immunostimulatory cytokines. However, they can also act as immunosuppressive agents, particularly in certain disease models. For example, tolerosomes, MHC Class-II positive vesicles derived from intestinal epithelial cells, canExtracellular vesicles (EVs), including exosomes, are small membrane vesicles derived from multivesicular bodies or the plasma membrane. They contain proteins, lipids, and nucleic acids that are transferred between cells, playing crucial roles in intercellular communication. EVs are involved in various physiological processes and have significant roles in immune regulation, both in non-immune and immune cells. This review focuses on the role of EVs in modulating immune responses and their therapeutic applications.
**Biogenesis and Traffic of Exosomes:**
Exosomes are generated by inward budding of the endosomal membrane, leading to the formation of intraluminal vesicles (ILVs) inside endosomes. These ILVs are then released as exosomes through the secretory or lysosomal pathways. The generation of exosomes involves the sorting of proteins and lipids into the endosomal membrane, delivery of cargo into ILVs, and excision of ILVs. Monoubiquitination of transmembrane proteins directs them to ILVs, which are then captured by the endosomal sorting complex for transport (ESCRT) machinery. Exosome biogenesis can occur through alternative mechanisms, such as sphingolipid-containing lipid rafts in the MVB membrane.
**Extracellular Vesicles in Antigen Presentation:**
EVs can directly or indirectly present antigens to T cells. Direct antigen presentation occurs when EVs carry MHC Class-I and Class-II molecules, which can stimulate CD8 and CD4 T cells, respectively. Indirect antigen presentation involves the transfer of p-MHC complexes to antigen-presenting cells (APCs) through exosome-mediated mechanisms. This can be facilitated by the interaction of EVs with DCs, which enhance the T-cell stimulatory activity of exosomes.
**Pathogenic and Native Antigens:**
EVs can transfer pathogenic antigens to APCs, promoting tumor-specific immune responses. For example, tumor-derived EVs containing native tumor antigens can be taken up by DCs and processed for cross-presentation to tumor-specific CTLs. Additionally, EVs can carry native antigens, such as those from viruses or bacteria, which can be presented to T cells.
**RNA Transfer:**
EVs also serve as carriers of genetic information, including mRNAs and small non-coding RNAs (ncRNAs). The transfer of RNAs from EVs to target cells involves docking and fusion of the vesicle membranes. This mechanism allows for the horizontal propagation of post-transcriptional regulation among APCs and other cell types.
**Activation and Immunosuppression:**
EVs can activate immune responses by promoting the maturation of DCs and macrophages, as well as by delivering immunostimulatory cytokines. However, they can also act as immunosuppressive agents, particularly in certain disease models. For example, tolerosomes, MHC Class-II positive vesicles derived from intestinal epithelial cells, can