However, unlike other EVs, cytoplasts have migratory and phagocytic capacity84. Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. Biol. Recent technical progress has led to the development of novel platforms by which up to 35 different marker molecules per single EV can be detected, which may boost the development of the EV field significantly. As a novel approach, mRNAs encoding SARS-CoV-2 spike and nucleocapsid proteins were loaded into small EVs, which induced immunity to SARS-CoV-2 in mice151. Extracellular vesicles: the growth as diagnostics and therapeutics; a 8, 1985 (2017). Get the most important science stories of the day, free in your inbox. For example, apoptotic exosome-like vesicles can induce autoantibodies to the basement membrane heparan sulfate proteoglycan perlecan (also known as HSPG2) in naive mice; these antibodies are known to be involved in graft rejection and, indeed, increased perlecan-specific antibody production results in allograft inflammation in mice transplanted with MHC-mismatched aortic grafts103. CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity. In fact, the production of adenosine by CD73 was found to be essential for the immunoregulatory function of EVs generated by Treg cells58. J. Mol. Donor tissue-specific exosome profiling enables noninvasive monitoring of acute rejection in mouse allogeneic heart transplantation. Cell Biol. Nat. In addition to T cells, DCs are also a target for Treg cell-derived EVs. Since their initial description, a previously unexpected biophysical, biochemical and functional heterogeneity of EVs has been discovered2,6,7. J. Biol. Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. In patients with melanoma, exosome-associated PDL1 distinguishes responders from non-responders to anti-PD1 therapy61. Cardiovasc. DC-derived EVs were shown to present the major cat allergen Fel d 1 and to induce allergic responses87. A special type of ectosome, known as ciliary ectosomes, are shed from the plasma membrane of cilia. Importantly, under experimental conditions, the proteasomes of platelet-derived EVs could process exogenous antigen and load the resulting peptides onto MHC classI molecules, leading to the proliferation of antigen-specific CD8+ T cells44 (Fig. C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Extracellular Vesicles: Role in Inflammatory Responses and - Hindawi Importantly, these patients also had increased amounts of cell-free DNA associated with EVs, suggesting a potential role of EVs in triggering and stimulating autoimmunity97. Schmidt-Arras, D. & Rose-John, S. Endosomes as signaling platforms for IL-6 family cytokine receptors. Cross-presentation of exogenous antigens on MHC classI complexes to CD8+ T cells has an important role in immunity against viruses and tumours and in the immune response upon vaccination and tolerance induction. Regulatory T (Treg) cells release EVs that contribute to the immunosuppressive activity of these cells by various mechanisms such as by surface expression of CD73. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. 9, 3630 (2018). Nat. Nat. Ectosomes include small-sized EVs (such as small ectosomes and arrestin domain-containing protein 1-mediated microvesicles), medium-sized microvesicles and the larger-sized apoptotic bodies. The extracellular vesicle generation paradox: a bacterial point of view. Fernndez-Messina, L. et al. For example, allergen-carrying pollensomes are naturally released by pollens of olive and ryegrass86. Lett. Extracellular vesicles (EVs) are heterogeneous, phospholipid membrane-enclosed structures. Bacterial outer membrane vesicles and vaccine applications. Springe. Zhang, Q. et al. Allergy 75, 12601263 (2020). Nat. Furthermore, both the EV-associated adenosine-generating ectoenzymes (CD39 and CD73) and the adenosine cargo of EVs are considered key mediators of immunosuppression in the tumour microenvironment116. EV-associated immune-checkpoint molecules (such as PDL1) may interfere with antitumour immunity and response to immunotherapy (as reviewed recently117). J. Extracell. Serum EV-associated miR-451a and miR-25-3p and soluble TWEAK (also known as TNFSF12) are candidate biomarkers in early rheumatoid arthritis156. CAS The immunoregulatory role of stem cell-derived EVs deserves particular attention. Stem cell-derived and progenitor cell-derived EVs have been shown to inhibit the functions of a wide range of immune cells (including T cells and B cells, natural killer (NK) cells, DCs, and monocytes and macrophages)62. Strategies to Isolate Extracellular Vesicles from Gram - Springer The immunogenicity of outer membrane vesicles has already been harnessed in two licensed vaccines against Neisseria meningitidis serogroup B124,125: Bexsero, developed by Novartis, and VA-MENGOC-BC, developed by the Finlay institute in Cuba66. Microbiol. Cell Death. Methods 18, 10131026 (2021). Donor dendritic cell-derived exosomes promote allograft-targeting immune response. Commun. 4, 594600 (1998). In a similar manner, microbial EVs are also expected to help protect against complement-mediated lysis of the microorganism. J. Immunol. Mast cells are key players in allergic responses. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. Sci. TKP2020-NKA-26. Certain EV-associated microRNAs (miR-16, miR-302d-3p, miR-378e, miR-570-3p, miR-574-5p, miR-579 and miR-25-3p) are candidate biomarkers for type 1 diabetes155. This inhibits the development of myeloid derived suppressor cells (MDSCs) and increases the co-stimulatory and antigen-presenting capacity of dendritic cells (DCs) in the tumour microenvironment to enhance antitumour immune responses128. Recent data showed that TCR signalling-induced T cell trans-synaptic vesicles contain greater levels of immune effectors (TCR, CD40L, RNA-binding proteins and miRNAs) than do constitutively released EVs49. 2c). The Journal of Extracellular Vesicles publishes open access research on extracellular vesicles, including microvesicles, exosomes, ectosomes and apoptotic bodies.Journal of Extracellular Vesicles is the official journal of the International Society for Extracellular Vesicles. PubMed Cell Res. Contribution of bacterial outer membrane vesicles to innate bacterial defense. Rep. 6, 36479 (2016). Demonstration of the antigen-presenting capacity of EVs was the first milestone discovery showing that EVs might have important roles in adaptive immunity. Semin. Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes. Extracellular vesicles (EVs) are membrane-coated particles released by every type of cell, which can carry content that affects the functioning of other tissues. The surface glycans of fungal EVs are also PRR ligands, as are the metalloproteinase GP63 and thrombospondin 1 (TSP1) on parasite-derived EVs70. In addition to their tissue repair-promoting properties, these EVs have a broad immunosuppressive potential. 11, 969985 (2011). Sci. However, definitive molecular markers of the different biogenetic routes are not yet available, and operational terms have been suggested to distinguish EV types based on their biophysical or biochemical properties2. The key role of miRNAs and exosomes in Treg cell-mediated suppression of CD4+ T cell responses was established using Dicer-deficient Treg cells and RAB27A and RAB27B double-deficient Treg cells, in which miRNA and exosome biogenesis were disrupted, respectively59. The broad term of bacterial extracellular vesicles is increasingly used to refer to all EVs released by bacteria5. Dis. J. Extracell. Wahlgren, J. et al. Critical role of extracellular vesicles in modulating the cellular effects of cytokines. Ther. Saliba, D. G. et al. Journal of Extracellular Biology is an official journal of the International Society for Extracellular Vesicles. The importance of exosomal PDL1 in tumour immune evasion. We discuss later how this feature of stem cell-derived and progenitor cell-derived EVs is being exploited in EV-based therapeutic approaches. By contrast, EVs, owing to their small size and their ability to cross biological barriers, can achieve efficient penetration of solid tumours. Cell Dev. Here, we have highlighted some of the key recent advances in our understanding of the roles of EVs in the immune system. Journal of Extracellular Vesicles - Impact Factor, Overall Ranking Mittelbrunn, M. et al. Zitvogel, L. et al. 126, 28052820 (2016). Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Med. B cells can also establish antigen-presentationsynapses with T cells. The release of EVs is evolutionarily conserved from Gram-negative and Gram-positive bacteria, fungi and parasites to humans66. J. Immunol. Med. Nucleic Acids 26, 987996 (2021). Challenges and directions in studying cell-cell communication by extracellular vesicles. Chen, G. et al. Another example of how bacterial EVs can be harnessed for therapeutic purposes is the use of probiotic-derived EVs, for example from Bifidobacterium longum, Clostridium butyricum and Lactobacillus plantarum WCFS1. Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets. J. Early prediction of COVID-19 severity using extracellular vesicle COPB2. These anti-inflammatory effects are due, for example, to the release of the lipopolysaccharide (LPS) co-receptor CD14 on macrophage-derived EVs, leading to decreased CD14 levels on the macrophage cell surface and decreased responsiveness to LPS as well as to the downregulation of nuclear factor-B (NF-B) activation in LPS-stimulated macrophages by HSPA12B-containing endothelial cell-derived EVs25. 43, 24302440 (2013). Morelli, A. E., Bracamonte-Baran, W. & Burlingham, W. J. Donor-derived exosomes: the trick behind the semidirect pathway of allorecognition. In addition to forming antigen-presentation synapses with T cells, B cells also establish synapses with follicular dendritic cells (FDCs) for the purpose of antigen capture and/or processing. Marki, A. & Ley, K. The expanding family of neutrophil-derived extracellular vesicles. 23, 12401254 (2021). Characterizing different probiotic-derived extracellular vesicles as a novel adjuvant for immunotherapy. Immunol. 15, 4067 (2020). However, many questions remain unanswered. This study was supported by the Hungarian Thematic Excellence Programme No. Garcia-Contreras, M. et al. 13, 405 (2022). Of note, the same population of neutrophils can secrete either pro-inflammatory or anti-inflammatory EVs, with clustering of the complement receptor Mac1 (CD11BCD18) on neutrophils functioning as a switch from anti-inflammatory to pro-inflammatory EV production81. Tumor-derived exosomes antagonize innate antiviral immunity. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Mol. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Rev. Sci. Oncosomes are large EVs produced by tumour cells. Di Vizio, D. et al. Interspecies outer membrane vesicles (OMVs) modulate the sensitivity of pathogenic bacteria and pathogenic yeasts to cationic peptides and serum complement. Stein, J. M. & Luzio, J. P. Ectocytosis caused by sublytic autologous complement attack on human neutrophils. In vivo, the B cellFDC synapse contains pMHC classII-carrying exosomes attached to the FDC surface. Busatto, S., Morad, G., Guo, P. & Moses, M. A. The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier. Currently, EVs are broadly being considered as potential immune therapies for several clinical conditions having immune or inflammatory components (Table2), including, recently, COVID-19 (Box2). Extracellular Vesicles in Blood: Sources, Effects, and - PubMed Invest. Stenqvist, A. C. et al. Int. EVs are implicated in allergic responses both as carriers of allergens and as modulators of the allergic response. The effects of EVs depend on the donor cell type and the phase of sepsis in which the EVs are analysed. 12, 710372 (2021). Rev. Allergy Clin. Arya, S. B., Chen, S., Jordan-Javed, F. & Parent, C. A. Ceramide-rich microdomains facilitate nuclear envelope budding for non-conventional exosome formation. Immunology 146, 217233 (2015). Nat. All of the immune cell types that participate in inflammation can secrete EVs, which in turn have multiple roles in inflammatory processes. Antibacterial effect of microvesicles released from human neutrophilic granulocytes. Annu. Mathieu, M. et al. Slider with three articles shown per slide. Tumour cell-derived EVs also inhibit the maturation of DCs by inducing the production of IL-6 (ref.110), inhibit NK cell responses by downregulating NKG2D expression on NK cells via EV-associated TGF1 (ref.111), and induce apoptosis of CD8+ T cells via EV-associated FASL, TRAIL or PDL1 (refs.112,113). Yu, S. et al. & Gay, S. Emerging role of extracellular vesicles in inflammatory diseases. EVs are suggested to have important roles in T cell development, with the majority of thymic EVs being released by thymic epithelial cells. When rolling on endothelial surfaces, neutrophils leave behind tethers that break off and give rise to elongated neutrophil-derived structures (ENDs) that ultimately become spherical. Platelet-derived EVs also have co-stimulatory molecules (CD40, CD40L and OX40L) on their surface. 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). 2a). Nat. Chem. Manning, A. J. Engineering extracellular vesicles enriched with palmitoylated ACE2 as COVID-19 therapy. Based on their biogenesis, we distinguish two basic types of EV (Fig. Of note, EVs also include vesicles generated by different cell death mechanisms (such as apoptosis, necroptosis or pyroptosis). Edit I. Buzas. International guidelines for EV separation and characterization are now available and are regularly updated2. Vincent-Schneider, H. et al. The outer membrane vesicles released by Gram-negative bacteria have, among other functions, roles in quorum sensing and horizontal gene transfer, and they carry toxins and other virulence factors. Recent data have shown that IL-33, a cytokine known to induce TH2 cell differentiation, is released by airway epithelial cells on the surface of exosomes90. J. Inflammasome activation during pyroptosis induces a marked release of exosomes, and a connection has been established between inflammasome-mediated cleavage of Rab-interacting lysosomal protein (RILP) and the selective loading of microRNAs (miRNAs) into EVs27. . Szajnik, M., Czystowska, M., Szczepanski, M. J., Mandapathil, M. & Whiteside, T. L. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). In this study, in addition to the proliferation and effector-memory differentiation of CAR T cells promoted by RN7SL1, the immunostimulatory activity of CAR T cell-derived EVs substantially supported the activity of CAR T cells, resulting in the efficient rejection of solid tumours even with CAR antigen loss128. Front. An additional aspect of the relationship between EVs and cytokines is that EVs can carry various cytokines, either on their surface (for example, tumour necrosis factor (TNF) bound to the TNF receptor, or CCL2 and transforming growth factor- (TGF) bound to glycosaminoglycans)141 or as their internal cargo142. 89, 125131 (2003). b | CAR T cells can be engineered to express the pattern recognition receptor agonist endogenous RN7SL1 RNA. J. Mol. J. Mol. Immune complexes exposed on mast cell-derived nanovesicles amplify allergic inflammation. More than half of patients with sporadic systemic lupus erythematosus associated with nephritis have decreased activity of the deoxyribonuclease DNASE1L3 in the circulation as a result of neutralizing autoantibodies to this enzyme, which leads to reduced clearance of degraded self-DNA. 29, 747754 (2020). Mol. PubMedGoogle Scholar. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Cell 184, 49814995.e14 (2021). Of note, under adverse conditions in the tumour microenvironment, such as during hypoxia or nutrient restriction, adaptive immunogenic stress responses of tumour cells are induced (including autophagy, endoplasmic reticulum stress and the DNA damage response), which increase the release of EVs with an altered molecular composition. Immunity 41, 89103 (2014). SCIMAGO SJR: 4.878. Vesicles 7, 1535750 (2018). T cell surface microvilli are found at the T cellAPC contact interface and were originally considered to be structures to screen and/or attach to the surface of APCs. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Organ Transplant. Front. Moreover, there is evidence that tumour-derived EVs may have unexpected effects on the antiviral immunity of patients with cancer by transferring growth factor receptors of the tumour to a select group of leukocytes. Immune cell-derived EVs released by tumour-associated macrophages, DCs, Treg cells, NK cells, B cells and T cells are also involved in antitumour immunity107. Thymic exosomes promote the final maturation of thymocytes. Kuipers, M. E., Hokke, C. H., Smits, H. H. & Noltet Hoen, E. N. M. Pathogen-derived extracellular vesicle-associated molecules that affect the host immune system: an overview. Nat. Elife 4, e05242 (2015). Kovcs, . F. et al. Nat. A. Article In a recent approach, CAR T cells were engineered to express the endogenous non-coding RNA RN7SL1 at high levels (Fig. Vesicles 10, e12050 (2020). Immunol. Of note, soluble mediators of innate immunity also have important EV-related functions. a | Chimeric antigen receptor (CAR) T cells release extracellular vesicles (EVs) carrying surface CARs. This effect of mast cell-derived EVs on type 2 innate lymphoid cells has been attributed to the miRNA miR103a-3p, which is enriched in mast cell-derived EVs. Cell 57, 974994.e8 (2022). Nat. EVs are released by all cellular organisms. Esser, J. U. et al. More. The RNA binding protein FMR1 controls selective exosomal miRNA cargo loading during inflammation. Plasma EVs display antigen-presenting characteristics in patients with allergic rhinitis and promote differentiation of Th2 cells. In mice and in Syrian hamsters, the intranasal administration of a vaccine based on bacterial outer membrane vesicles induced both mucosal and systemic immune responses to SARS-CoV-2 (ref.149). van der Ley, P. A., Zariri, A., van Riet, E., Oosterhoff, D. & Kruiswijk, C. P. An intranasal OMV-based vaccine induces high mucosal and systemic protecting immunity against a SARS-CoV-2 infection. Johnson, L. R. et al. 183, 340351 (2009). Google Scholar. Rossaint, J. et al. EVs carry numerous autoantigens that are implicated in autoimmune diseases, such as DNA and nucleosomes, DEK, -enolase, citrullinated proteins, Sjgren syndrome-related antigen A (SSA; also known as Ro or TRIM21), Sjgren syndrome-related antigen B (SSB; also known as La) and Smith antigen (Sm)94,95. Proc. Vesicles 10, e12080 (2021). Rampinelli PG, Correa JR and Almeida PE (2021) Impact of the Extracellular Vesicles Derived From Trypanosoma cruzi: A Paradox in Host Response and Lipid Metabolism . This knowledge may be exploited to develop new biomarkers for disease and therapy monitoring as well as new therapeutic tools and delivery vehicles as indicated by recent clinical trials in this area. Semin. 21, 4072 (2020). 23, 1461 (2022). Internet Explorer). Finally, an interesting novel finding is that medium-sized platelet-derived EVs (microvesicles) can function as complete functional units of antigen presentation; they not only carry pMHC classI complexes and co-stimulatory molecules (CD40L, CD40 and OX40L) on their surface but also contain functional 20S proteasomes to enable peptide generation for antigen presentation. EMBO Rep. 21, e48925 (2020). Adv. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Timr, C. I. et al. Theranostics 11, 85708586 (2021). Shelke, G. V. et al. In addition to these mechanisms for direct and semi-direct (cross-dressing-mediated) antigen presentation by EVs, vesicles carrying pMHC as well as intact antigen can be internalized and processed efficiently by antigen-presenting cells (APCs) for indirect antigen presentation40. Journal of Extracellular Vesicles - Impact Factor & Score 2023 59, 20372046 (2018). I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. Of note, it is not only single virus particles that can be encapsulated in EVs the en bloc release of large, membrane-cloaked virus clusters also enables viruses to hide from immune recognition13. 183, 37203730 (2009). Numerous studies have described strategies to prevent or ameliorate SARS-CoV-2 infection by EVs or to use EVs as predictive biomarkers for disease severity. 181, 15731584 (2012). Early studies showed that B cell-derived EVs can present allergen peptides and induce a TH2 cell response89. EVs are secreted by almost all cell types; they can transfer information between nearby or distant cells, and they are highly abundant in body fluids. The impact score (IS), also denoted as Journal impact score (JIS), of an academic journal is . Admyre, C. et al. It is also increasingly recognized that EV biogenesis can intersect with viral egress13, secretory autophagy, the cellular senescence-associated secretory phenotype and the DNA damage response14. Research Ranking (Biology and Biochemistry) 96. The power of imaging to understand extracellular vesicle biology in vivo. The ectoenzymes CD39 and CD73 generate adenosine from ATP, which impairs cytotoxic T lymphocyte (CTL) responses and antigen presentation by dendritic cells (DCs). J. Immunol. EV-associated molecular signatures are proposed as candidate biomarkers in lung, heart, kidney and liver transplantation, and pancreatic island transplant rejection as reviewed recently104. This study shows the cross-presentation capacity of platelet-derived EVs, which contain a functional proteasome. In individuals with asthma, airway epithelial cell-derived EVs and EV-associated contactin 1 were identified as inducers of DC recruitment and activators of monocyte-derived DCs91.