The twenty-first century has witnessed major developments in the field of extracellular vesicle (EV) research, including significant steps towards defining standard criteria for the separation and detection of EVs. The recent recognition that EVs have the potential to function as biomarkers or as therapeutic tools has attracted even greater attention to their study. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. Researchers from Semmelweis University discuss the roles of EVs in basic processes of innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells. They also highlights key progress related to deciphering the roles of EVs in antimicrobial defence and in allergic, autoimmune and antitumour immune responses. Finally, they focus on the relevance of EVs to immunotherapy and vaccination, drawing attention to ongoing or recently completed clinical trials that aim to harness the therapeutic potential of EVs.
Immunoregulatory functions of extracellular vesicles
Immunoregulatory molecules on the surface of extracellular vesicles (EVs), including the immune-checkpoint molecules programmed death ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) and the apoptosis-inducing ligands FASL and TNF-related apoptosis inducing ligand (TRAIL), interact with cognate ligands and receptors expressed by T cells and natural killer (NK) cells to inhibit their activity or induce apoptosis. The ectoenzymes CD39 and CD73 generate adenosine from ATP, which impairs cytotoxic T lymphocyte (CTL) responses and antigen presentation by dendritic cells (DCs). Regulatory T cell-derived EVs contain EV-associated microRNAs (miRNAs) that suppress CD4+ T cell responses (such as miR-155, Let7b and Let7d) or modulate cytokine production by DCs (such as miR-150-5p and miR-142-3p). The immunosuppressive cytokine transforming growth factor-β (TGFβ), which associates with betaglycan on the surface of EVs, activates regulatory T cells and myeloid derived suppressor cells (MDSCs) and downregulates expression of the activating receptor NKG2D on NK cells. EVs carrying MICA and MICB, which are ligands for NKG2D, can also lead to its downregulation on NK cells.