Extracellular vesicles and immune modulation.

Abstract

Extracellular vesicles (EV) come in many forms, and have many names: exosomes, microvesicles, microparticles, cell-associated particles, apoptotic vesicles, oncosomes, prostasomes … the list is long. These extremely heterogeneous vesicles contain a wide range of molecules, including proteins, lipids and nucleic acids, can probably be released from any cell, and traditionally were thought of as a cellular waste disposal mechanism. However, it is increasingly obvious that EV are an integral part of a cell, their formation and composition are highly regulated, and they are a critical component of inter-cellular communication. This Special Feature examines our growing understanding of the importance of EV in blood and immune cell function. Exosomes released by professional antigen-presenting cells (APC) can have peptide-loaded MHCII and co-stimulatory molecules on their surface, and carry selected antigens and cytokines in the lumen. Able to act at a distance as well as locally, these exosomes act as an extension of the APC. Transfer of these peptide-loaded MHCII and costimulatory proteins from the exosome to the target cell membrane upon fusion can result in “cross-dressing” of the target cell. Kain and colleagues1 examine exosome biogenesis in APC, and the impact that exosome composition has on antigen presentation and adaptive immune cell activation. The effect of EV on immune-mediated pathology in infectious disease is reviewed by Grau and colleagues.2 T-cells, macrophages, endothelial cells, epithelial cells, erythrocytes and others are all targets for EV released in response to pathogen infection. EV are functionally diverse, mediating both pathogenic and protective effects in bacterial, parasitic and viral infection. The role of EV in parasitic infection is extended by Loukas and colleagues,3 who focus on the EV produced by helminth worms, and the role these EV play in modifying the host immune system. Successful colonization of the host requires complex manipulation of the environment, and helminth-derived EV are important in this. During pregnancy, the fetus similarly modifies the environment by manipulating the host maternal immune system. Chamley and colleagues4 review recent work focused on EV derived from the placenta in feto-maternal communication. The placenta is essentially an allogenic tissue transplant that requires immune tolerance for survival, with evidence that placental-derived EV may underlie these adaptations. McLellan and colleagues5 describe the role of EV in coagulation, an essential physiological process for blood cells. While normal coagulation is protective, inappropriate coagulation—thrombosis—is pathogenic. Cancer patients have a higher risk of thrombosis than healthy people, which is increased even more with chemotherapy. The subset of apoptotic vesicles released by the cancer cell, particularly after chemotherapy, are believed to play an essential role. Even prior to treatment, cancer cells release a multitude of other EV, which are used to modulate the immune environment and drive immunosuppression, even at distant sites. Using colorectal cancer as an example, Danielson and colleagues6 look at the multitude of ways cancer cells use EV to successfully modify their environment. Far from merely being “waste disposal” mechanisms, EV are in fact functional extensions of a cell, as carefully regulated as any other cellular process. Any analysis of cellular response to stimulus disregards the EV at its peril! Furthermore, the distribution of EV into the wider extracellular environment and their importance in cell-to-cell communication makes them an attractive target for therapeutic intervention, whether this utilizes EV as a delivery mechanism, or whether it blocks—or enhances—intercellular messages. Research is well underway to bring some much-needed clarity to the complexity of EV biology, and to realize the potential of manipulating this somewhat overlooked part of a cell. None declared.