Exosomes and other extracellular vesicles in host–pathogen interactions

Review8 December 2014free access Exosomes and other extracellular vesicles in host–pathogen interactions Jeffrey S Schorey Corresponding Author Jeffrey S Schorey Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Yong Cheng Yong Cheng Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Prachi P Singh Prachi P Singh Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Victoria L Smith Victoria L Smith Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Jeffrey S Schorey Corresponding Author Jeffrey S Schorey Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Yong Cheng Yong Cheng Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Prachi P Singh Prachi P Singh Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Victoria L Smith Victoria L Smith Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA Search for more papers by this author Author Information Jeffrey S Schorey 1, Yong Cheng1, Prachi P Singh1 and Victoria L Smith1 1Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA *Corresponding author. Tel: +1 574 631 3734; Fax: +1 574 631 7413; E-mail: [email protected] EMBO Reports (2015)16:24-43https://doi.org/10.15252/embr.201439363 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract An effective immune response requires the engagement of host receptors by pathogen-derived molecules and the stimulation of an appropriate cellular response. Therefore, a crucial factor in our ability to control an infection is the accessibility of our immune cells to the foreign material. Exosomes—which are extracellular vesicles that function in intercellular communication—may play a key role in the dissemination of pathogen- as well as host-derived molecules during infection. In this review, we highlight the composition and function of exosomes and other extracellular vesicles produced during viral, parasitic, fungal and bacterial infections and describe how these vesicles could function to either promote or inhibit host immunity. Glossary APC antigen-presenting cell APOBEC3G apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G BALF bronchoalveolar lavage fluid BAT3 HLA-B-associated transcript 3 BCG bacillus Calmette–Guérin BMDCs bone marrow-derived dendritic cells CCR5 C-C chemokine receptor type 5 CD cluster of differentiation CFP culture filtrate protein CIA collagen-induced arthritis CMV cytomegalovirus CTL cytotoxic T lymphocyte CXCR4 C-X-C chemokine receptor type 4 DC dendritic cell DT diphtheria toxin DTH delayed-type hypersensitivity EBA-175 erythrocyte binding antigen 175 EBV Epstein–Barr virus EM electron microscopy ESCRT endosomal sorting complexes required for transport FACS fluorescence-activated cell sorting Fas/FasL Fas and Fas ligand HCV hepatitis C virus HEK human embryonic kidney HIV human immunodeficiency virus HLA-DR major histocompatibility complex, class II, DR beta 1 HMC-1 human mast cell line-1 HSP heat-shock protein HSV herpes simplex virus ICAM1 intercellular adhesion molecule 1 iDC immature DC IFN interferon IL interleukin ILVs intraluminal vesicles JNK c-Jun N-terminal kinase LAM lipoarabinomannan LBPA lysobisphosphatidic acid LFA-1 lymphocyte function-associated antigen 1 LMP1 latent membrane protein 1 LPS lipopolysaccharide M.tb Mycobacterium tuberculosis MAP kinase mitogen-activated protein kinase MC/9 Mus musculus mast cell line MCP-1 monocyte chemotactic protein 1 mDC mature DC MFG-E8 milk fat globule-EGF factor 8 protein MHC major histocompatibility complex miRNA microRNA MVB multivesicular bodies MyD88 myeloid differentiation primary response gene (88) NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NK natural killer NLRP3 NACHT, LRR and PYD domains-containing protein 3 NPC nasopharyngeal carcinoma PAMP pathogen-associated molecular pattern PBMC peripheral blood mononucleated cells PIM phosphatidylinositol mannoside PRR pattern recognition receptor RANTES regulated on activation, normal T cell expressed and secreted RBC red blood cell RILP rab-interacting lysosomal protein RNP ribonucleoprotein ROS reactive oxygen species SNARE SNAP (soluble NSF attachment protein) REceptor TAR trans-activation response TB tuberculosis TCR T-cell receptor TF tissue factor Tim4 T-cell immunoglobulin mucin protein 4 TLR toll-like receptor TNF tumor necrosis factor VAMP7 vesicle-associated membrane protein 7 WT wild-type Introduction The ability of the immune system to recognize and respond to pathogenic organisms is essential for the body's ability to control an infection. Divided into the innate and acquired branches, immune responses elicit protection against most pathogenic invaders. A number of mechanisms for how the immune system accomplishes this protection have been defined. Cytokines and chemokines, as well as other inflammatory mediators produced by infected or resident immune cells, clearly recruit and activate leukocytes and other cells, culminating in the elimination of the invading organism. Pathogen-derived products are major drivers of both the innate and acquired immune response. The microbial components that trigger the innate immune response do so either directly by inducing the production of immune effector molecules like reactive oxygen species or indirectly through stimulating the production of cytokines and chemokines. These microbial components that promote the innate immune response are generally defined as PAMPs (pathogen-associated molecular patterns). PAMPs are structurally diverse molecules found across many species of non-pathogenic and pathogenic organisms and include lipids, proteins, carbohydrates and genetic material. Pattern recognition receptors (PRRs), such as TLRs, present on leukocytes and various non-immune cells, can bind to PAMPs, thereby initiating cell-signaling cascades. This ultimately leads to the activation of an immune response against the pathogen. The importance of PRRs in the recognition and response to pathogens has been shown in both animal infection models and human studies 1. Given their role in immunity, it is not surprising that pathogenic organisms have evolved methods to modulate the binding and/or signaling through the PRRs as mechanisms to promote their virulence and evade surveillance by the immune system 23. The mechanisms for exposure of PAMPs to PRRs differ between intracellular and extracellular pathogens. For extracellular pathogens, PAMPs are released through an active process or through shedding or death of the organism. The released factors can then directly bind PRRs on immune cells, stimulating or inhibiting host responses. In contrast, intracellular pathogens, such as Mycobacteria, Salmonella and Toxoplasma, produce PAMPs which—like the pathogens they are derived from—have limited exposure to the immune system. Nevertheless, the host does respond to these PAMPs, likely through multiple mechanisms. An obvious source of interaction is the cell invasion process 456. Moreover, a pathogen may be present in the extracellular milieu between host cell entries, allowing for release of PAMPs. This is likely a particularly important mechanism for viral proteins and viral RNA/DNA. The ability of HIV to invade host cells is known to be heterogeneous depending on the interactions with its cellular receptors; a slower invasion leads to increased phagocytosis of the virion by phagocytic cells 7. However, some intracellular pathogens like Listeria monocytogenes can go from cell to cell without being exposed to the extracellular environment 8. Debris from necrotic infected cells or release of apoptotic bodies from infected cells can also disseminate pathogenic components to surrounding cells/tissue 9. However, what has become increasingly clear is that exosomes and other extracellular vesicles released from infected cells, as well as from the pathogens, likely play an important role in this dissemination process 101112. These components not only include PAMPs, but also T- and B-cell antigens, as well as pathogen-derived toxins. In this review, we briefly introduce exosomes and how they are generated, as well as their role in non-infectious diseases, with an emphasis on their immune modulatory activity. We then focus in-depth on the production and activity of exosomes and other extracellular vesicles during infection, and how these vesicles could benefit the host immune response but also be used to promote pathogen survival. Finally, we discuss their therapeutic potential, including their use as vaccines and diagnostic tools. Extracellular vesicles Extracellular vesicles are broadly defined as membrane-bound vesicles released from cells. Those produced during an infection can be pathogen or host derived. The former include, for example, outer membrane vesicles from gram-negative bacteria and membrane vesicles from gram-positive bacteria. The content and function of these bacteria-generated vesicles has recently been under intensive investigation and excellently reviewed elsewhere 131415. Although these vesicles likely play an important role during the course of an extracellular bacterial infection, their role in intracellular pathogen infections is less clear, as mechanisms to transport the vesicles outside the host cell are not known. Parasitic and fungal pathogens also release extracellular vesicles, which may function in modulating the immune response 1617. Host-derived vesicles are present during viral, bacterial, parasitic and fungal infections. These vesicles have different origins and composition and, based on their biogenesis, are divided into three main categories: apoptotic bodies, exosomes and microvesicles. All three of these cell-derived vesicles are enclosed by a lipid bilayer, but vary in size (from 30 to 2,000 nm in diameter), as well as in composition. In contrast to microvesicles, which are generated by budding from the plasma membrane 18, exosomes are derived from the endolysosomal pathway and have a unique lipid and protein makeup. Exosomes have been the most studied in the context of infection. An important note, however, is that exosome purity was not always analyzed in these studies, and therefore, the vesicle population may have consisted of both exosomes and microvesicles, which overlap in size and density. Nevertheless, we will use the terminology as defined in the original studies when discussing the results. Exosomes Exosomes are formed through the fusion of multivesicular bodies (MVBs) with the plasma membrane and subsequent release of intraluminal vesicles (ILVs) as exosomes (Fig 1). Exosomes are 30–100 nm vesicles, surrounded by a lipid bilayer, that have a density of 1.13–1.19 g/ml. Biophysically, exosomes are equivalent to cytoplasm enclosed in a lipid bilayer with the external domains of transmembrane proteins exposed to the extracellular environment. EM studies have demonstrated the fusion of the limiting membrane of MVB with the plasma membrane, as well as the release of ILVs, in different cell types of hematopoietic origin, such as Epstein–Barr virus (EBV)-transformed B cells 19, mastocytes 20, DCs 2122, platelets 23, macrophages 10 and cells of non-hematopoietic origin such as neurons and epithelial cells 242526. Exosomes can act locally or circulate through various bodily fluids, including blood and lymph, resulting in a systemic response 27. Exosomes were first identified in the culture media of reticulocytes 2829. However, over the past two decades, the study of exosomes has extended to most cell types, and they have been isolated from different organisms—including unicellular eukaryotes—suggesting that this is an evolutionarily conserved mechanism of cell–cell communication. The advantage of using exosomes for cell–cell communication stems from their complex composition, which allows more control over the communication process. Moreover, the presence of signaling lipids, proteins and various species of RNA within a single structure can lead to rapid and profound changes in the target cell, enabling a swift response to cellular perturbations, which can be local or systemic. These changes may be induced under physiological or pathological conditions. Although the complexity of exosomes has clear benefits to the organisms that produce them, it has made the study of their function exceedingly difficult, as the effect of an exosome or pool of exosomes is a result of all the different components within them, including lipids, proteins, carbohydrates and RNA. Moreover, the tools available to modulate exosome production and composition in vitro and in vivo are severely limited, hampering our ability to define exosome function in normal and diseased states. Nevertheless, we have gained important insights into exosome biogenesis, composition and function over the past decade, a decade that has seen a rapid expansion in publications on this type of extracellular vesicle. Figure 1. Exosome biogenesisLipids, proteins and nucleic acids are transported to MVBs and onto or into the intraluminal vesicles, which upon fusion of the MVB with the plasma membrane are released as exosomes. Originally identified as a way to release transferrin receptor from maturing reticulocytes, other plasma membrane proteins have been shown to be targeted to MVBs through various mechanisms and released on exosomes. RNA and cytoplasmic proteins are also transported to MVBs, although the mechanisms mediating this transport are less understood (indicated by dashed line). See Glossary for definitions. Download figure Download PowerPoint Exosome biogenesis A major mechanism for down-regulating and degrading plasma membrane receptors is through their endocytosis and trafficking to an MVB, which can subsequently fuse with the lysosome to mediate protein degradation 30. However, at least a subpopulation of MVBs can also fuse with the plasma membrane, resulting in the release of the intraluminal vesicles (ILV) as exosomes. Despite their discovery nearly three decades ago, the mechanism for MVB biogenesis and exosome release is still being defined. Several models have been suggested as a mechanism for ILV formation. Initial studies in yeast demonstrated a role for the ESCRT proteins 31. Although the ESCRT machinery has primarily been studied for its role in the endosomal sorting and degradation of ubiquitinated proteins, it has also been implicated in mediating membrane invagination 3233. Through its ubiquitin-interacting domains, ESCRT-0 clusters ubiquitinated proteins for delivery into MVBs 34. ESCRT-0 subsequently recruits ESCRT-1 to the endosomal membrane, which in turn recruits the remaining members of the ESCRT machinery, ESCRT-II and ESCRT-III 3536. Through the formation of polymeric filaments mediated by ESCRT-III, membrane invagination results in ILV formation 37 (for a recent review, see 38). Indeed, various studies support a role for the ESCRT machinery in exosome formation. Proteomic analysis of exosomes has demonstrated the presence of ESCRT machinery within exosomes, and knockdown of key components of ESCRT machinery can abrogate ILV formation and exosome release 39, although this is likely cell type-specific 4041. While this general model for MVB biogenesis has been well characterized, it is unclear whether this constitutes the major mechanism of MVB formation. A number of studies suggest there are ESCRT-independent mechanisms for MVB biogenesis and exosome release. In oligodendroglial cell lines, exosome formation is driven by the production of ceramide, rather than the ESCRT machinery 41. Stuffers and colleagues found that depleting specific subunits from the four ESCRTs complexes did not completely inhibit MVB formation 40. Furthermore, a mechanism independent of both ESCRTs and ceramide has been proposed. Studies by van Niel and colleagues found that the tetraspanin CD63, which is present on exosomes in high abundance, mediates cargo sorting and ILV formation 42. Additionally, CD81 has been demonstrated to mediate cargo sorting of tetraspanin ligands, such as Rac GTPase, although knockdown of this tetraspanin does not appear to alter MVB morphology or exosome secretion 43. These different observations suggest that the mechanism for exosome biogenesis and protein sorting may be cell type-specific or specific to different subpopulations of MVBs within a cell. In support of the latter, Stoorvogel and colleagues have shown that within immature DCs, the MHC molecules are targeted to MVBs that are low in cholesterol but enriched for lysobisphosphatidic acid, which are destined for lysosomal degradation. However, in mature DCs, MHC molecules are sorted into MVBs that are enriched in CD9 and cholesterol, which are targeted for fusion with the plasma membrane 44. Once MVBs are formed, their fusion with the plasma membrane is mediated by the cytoskeleton, fusion machinery—such as the SNARE proteins—and molecular switches (such as small molecular weight GTPases) 45. Rab GTPases are members of the Ras GTPase superfamily and are known to regulate four steps in membrane trafficking: vesicle formation, trafficking, tethering and fusion with target organelles. Almost 70 different Rab GTPases have been identified to date in mammalian cells 46. Several of these have been found on exosomes, including Rab5, Rab11, Rab27 and Rab35. Some of these Rab effectors have been experimentally shown to function in exosome release. Early studies suggested that Rab11 might function to promote MVB fusion with the plasma membrane in the K562 erythroleukemic cell line 47. More recent studies have implicated Rab35 in mediating MVB docking to the plasma membrane in neuralgia cells, where depletion of Rab35 resulted in a significant loss in exosome release 48. Rab27a and Rab27b were also shown to have different, but sometimes redundant, roles in MVB biogenesis, with Rab27a more implicated in mediating MVB docking to the plasma membrane 49. Although the Rab GTPases have been implicated in MVB trafficking and fusion, their role in the process is still under investigation and will likely be cell type-dependent, as well as dependent on the physiological/pathological state of the cell. Exosome composition Exosomes contain all types of biomolecules, including proteins, carbohydrates, lipids and nucleic acids. Their lipid and protein composition has been extensively analyzed by various techniques, including Western blotting, FACS, immuno-EM and mass spectrometry. Exosome composition will vary depending on the cell type of origin, its physiological/pathological state and even the cell site of origin, as seen in epithelial cells. Epithelial exosomes have different composition if they are released from the apical or basolateral surfaces 50. Cell type-specific markers can help define the exosome cellular origin; for example, the presence of T-cell or B-cell receptors is indicative of T-cell and B-cell origin, respectively. The exosome protein composition can also be informative of the existence of a pathology, as they can, for example, carry tumor antigens or inflammatory mediators. In addition, exosomes contain a number of common proteins, including Tsg101, Hsc70 and various tetraspanins 51, as well as proteins that participate in vesicle formation and trafficking, such as the LBPA-binding protein, Alix 52. Exosome lipid composition has also been well characterized. As for proteins, the ratios of the different lipids can vary between exosomes released from different cellular origins. In general, exosomes are enriched in lipids such as sphingomyelin, phosphatidylserine, gangliosides and cholesterol, as compared to plasma membranes and other intracellular membranes 53. A number of reviews have highlighted the protein and lipid content of exosomes 5455, and various databases have cataloged the protein, lipid and RNA content of exosomes (ExoCarta, http://www.exocarta.org/, Vesiclepedia, http://microvesicles.org/). Most recent studies have focused on exosomal RNA; the types of RNA and their nucleotide sequence, their ability to be transferred between cells, their function once transferred and the mechanism by which they are trafficked to MVBs and into exosomes. Pioneering studies by Valadi and colleagues showed that exosomes are enriched in mRNA and miRNA 56. More recent studies have identified other non-coding RNAs in exosomes, but limited amounts of DNA or ribosomal RNA 57. The exosomes derived from a human (HMC-1) and mouse (MC/9) mast cell lines were found to transport mRNA to neighboring mast cells. This mRNA was subsequently translated, indicating that it is biologically active 56. Exosomes released by immune cells have been shown to contain a selective repertoire of miRNAs that can be functionally transferred to recipient cells 5859. The source of these exosomes/extracellular vesicles were cultured cells 60 and body fluids 6162. Together, these data suggest that exosomes function as carriers of genetic information and that this genetic material plays a role in cell–cell communication. However, the exosomal RNA content differs both in quantity and in composition depending of the cellular origin and cellular environment. Eldh and colleagues found that the exosomes released by mast cells differ in their mRNA content after exposure to an oxidative stress, and oxidative stress resistance was induced in recipient cells 63. These results indicate that the incorporation of RNA into vesicles is a regulated event leading to selective packaging of RNA into exosomes and other extracellular vesicles 6465. The mechanism(s) responsible for the targeted loading of RNA into exosomes is still being defined and remains an active area of investigation. In addition to host components, a number of pathogen-derived components have been found on exosomes after cell or animal infection (Table 1). Unfortunately, we know very little about how these diverse pathogen-derived proteins, glycolipids, etc. are sorted to MVBs and onto exosomes (see Sidebar A). Much of our current understanding stems from studies of viruses, where viral assembly and exosome biogenesis share many similarities. For example, HIV assembly and release from infected cells depend on both ESCRT machinery and tetraspanin-rich lipid domains 6667. The presence of viral proteins in exosomes and the similarities in biogenesis and assembly suggest that a degree of ‘crosstalk’ or ‘hijacking’ could be responsible for sorting the viral proteins into exosomes. However, some viral proteins—such as the HIV protein Nef—may contain necessary signals to mediate their direct sorting into exosomes 68. For other types of pathogens, even less is understood. Some intracellular bacterial pathogens, such as Mycobacterium tuberculosis, are also known to interfere with host machinery implicated in exosome biogenesis, such as ESCRTs 69, although the extent to which this contributes to protein sorting during exosome biogenesis is unclear. Based on our observations, sorting of mycobacterial proteins seems to be independent of cell entry mechanisms, as mycobacterial proteins are found on exosomes whether added as free protein, and therefore taken in through an endocytic route, or expressed in mycobacteria, which enters by phagocytosis 11. This finding suggests that these mycobacterial proteins have the necessary ‘signal’ to be trafficked to the MVB during exosome biogenesis. However, further investigation is needed to shed light on potential sorting mechanisms. Table 1. Pathogen components present on exosomes/extracellular vesicles released from infected cells Pathogen Vesicle contents References HIV Gag proteins 119 Nef protein 68 121 123 124 TAR transcripts 120 EBV Viral RNAs 134 LMP1 129 LMP2a 130 CMV Glycoprotein B 138 Hepatitis C virus Viral RNAs 70 Viral RNA/proteins 141 142 Envelope glycoprotein E2 139 HSV Viral tegument proteins and various glycoproteins 146 Toxoplasma gondii PAMPs 10 Leishmania mexicana GP63 156 Proteomic analysis 156 Leishmania major GP63 157 Leishmania donovani GP63 158 Proteomic analysis 155 Plasmodium yoelii Proteomic analysis 160 Plasmodium falciparum EBA-175, EBA-181 162 Proteomic analysis 162 PfPTP2 163 Mycobacterium tuberculosis LAM, PIM 10 180 181 19 kDa lipoprotein 10 Proteomic analysis 11 mRNA J.S. Schorey, unpublished data Mycobacterium avium GPLs 182 Salmonella typhimurium LPS 10 Mycoplasma Lethal factor 195 Proteomic analysis 195 Viral RNAs have also been found within exosomes. HCV viral RNA transport to exosomes was found to be dependent on the ESCRT machinery and on Annexin A2, an RNA-binding protein involved in membrane vesicle trafficking 70. Similarly, EAP30—a subunit of ESCRT-II—controls HIV-1 RNA trafficking and gene expression through a complex formed by HIV-1 Gag, ESCRT-II and Staufen-1 71. The mechanism by which EAP30/ESCRT-II facilitates HIV-1 genomic RNA trafficking remains unclear, although—considering the roles for ESCRT-II in the nucleus 72—EAP30/ESCRT-II is likely part of the RNP complex that mediates the nuclear export of viral RNA. Other partners of EAP30, such as EAP45, have an RNA-binding domain that is likely conserved 7374, and RILP—which associates with EAP30—can also have an effect on the localization of viral RNA in the cytoplasm. EAP30/ESCRT-II could also contribute to the stability of cellular factors that are required for viral RNA trafficking. Exosomes as modulators of the immune response Most studies of exosomes and their effect on the immune response are in the context of cancer and autoimmunity. These studies have: (i) defined the host molecules that facilitate exosome transfer; (ii) characterized the presence of tumor antigens on exosomes and mechanisms by which these antigens can promote T-cell activation; (iii) defined the mechanisms by which some exosomes can induce T-cell anergy and deletion; and (iv) defined the RNA content within the exosomes, as well as characterized their transcriptional and translational effect on recipient cells 75. Other studies have characterized exosomes as drivers of an innate immune response, although significantly less work has been done in this area 76. Innate immunity Dendritic cells produce exosomes constitutively and have been implicated in the activation of the innate immune response (Fig 2). Exosomes from both immature and mature DCs contain multiple TNF superfamily members—such as TNF, FasL and Trail—on their surface, which directly bind to the surface receptors on NK cells to enhance their cytotoxic activity. However, the activation of NK cells is significantly stronger in response to exosomes released from activated DCs 77. Similarly, exosomes from DCs express BAT3 (HLA-B-associated transcript-3) and thus are recognized by the NK surface receptor, NKp30, leading to NK-cell activation 78. DCs activated by lipopolysaccharide (LPS) release extracellular vesicles that can stimulate epithelial cells to secrete chemokines—such as IL-8 and RANTES—which may be an important component in the pathogenesis of sepsis 79. DC-derived microvesicles have also been shown to induce NF-κB activation in microglia cells, which may play a role in the inflammatory response observed in the CNS during experimental autoimmune encephalomyelitis (EAE) 80. IL-1β, a major driver of the innate immune response, is produced as a pro-form and converted to its active form through cleavage by the inflammasome. The mature form is released by activated macrophages and DCs through a non-classical secretion pathway. Qu and colleagues propose that trafficking via exosomes may be one mechanism for IL-1β release, although this was not definitively proven because exosomes containing the mature IL-1β could not be isolated after ATP stimulation of bone marrow-derived macrophages 8182. In the presence of oxidized low-density lipoprotein (oxLDL)-conjugated immune complexes, macrophages release exosomes containing IL-1β, as well as increased levels of acid sphingomyelinase and HSP70, and these exosomes may promote the propagation of atherosclerotic plaques 83. These and other studies clearly demonstrate a role for exosomes/extracellular vesicles in regulating inflammatory and innate immune responses. As described below, their role is likely more pronounced in the context of an infection, as these exosomes could carry both host and pathogen components. Figure 2. DC-derived exosomes modulate innate and acquired immune responsesExosomes from mature DCs (mDCs) can provide antigen to T cells, stimulate innate immune responses in various immune and