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Page 4 of 20 Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27

Role of exosomes in innate immunity
Exosomes are thought to play an important role in the host immune response to infection. Reciprocal
cross-talk between platelets and neutrophils is enabled by neutrophil-derived exosome transfer of
arachidonic acid to platelets, which is enzymatically converted into thromboxane A2 (TxA2). Release of
TxA2 from platelets contributes to the upregulation of ICAM-1 on neutrophils, which binds to the EC
[41]
surface and enables their extravasation to the site of infection to engage microbes .
Exosomes are directly involved in immune signaling in as much as they can cargo pro-inflammatory
and anti-inflammatory cytokines to target cells [42-45] as well as stimulate the secretion of these cytokines
from recipient cells [35,46,47] . For instance, a recent study documented the role of apoptotic exosome-like
vesicles in promoting the synthesis of the pro-inflammatory IL-1β in macrophages, thereby contributing
[48]
to their activation . In contrast, exosomes have also been shown to promote the production of the anti-
inflammatory transforming growth factor-β (TGF-β) in macrophages leading to the inhibition of the innate
immune response [47,49] . Murine LPS-stimulated macrophages produce exosomes containing endoplasmic
reticulum aminopeptidase 1, TNF-a, IFN-g, and CCL3, which induces phagocytosis and nitric oxide
synthesis in adjacent recipient macrophages [47,50] , important cellular mediators in clearing the microbial
infection. Additionally, epithelial cell uptake of exosomes secreted by LPS-induced dendritic cells (DCs)
has been shown to stimulate their activation and subsequent release of cytokines and chemokines to further
the innate response [51,52] .

PAMPs are vital for recognition of pathogens and activation of immune cells and have been found inside
exosomes secreted by both infected cells [53,54] and pathogens [55-57] . Interaction of PAMP-containing exosomes
with the innate immune cells can induce inflammation. This has been observed in bacteria-infected
macrophages, which release exosomes-contained pathogen antigens, which in turn promote maturation of
[58]
DCs and secretion of pro-inflammatory cytokines .
Role of exosomes in adaptive immunity
Exosomes not only influence innate immune responses but can also play a marked role in adaptive
immunity by promoting immune activation or suppression. B-lymphocytes infected with Epstein-Barr
virus were the first immune cells discovered to release exosomes. These exosomes were shown to contain
peptide-bound MHC Class I and II, B7 co-stimulatory, and ICAM-1 adhesion molecules that could induce
[51]
a specific T cell response through the direct presentation of MHC Class II antigen . Later, DCs were also
found to release exosomes, possessing MHC Class I and II and T cell co-stimulatory molecules, leading to
direct antigen presentation and CD4+ and CD8+ T cell activation. DC-derived exosomes can also mediate
antigen presentation through bystander DCs, by either cross-dressing or internalization of the exosomes
and subsequent peptide transfer to the recipient cell MHC molecules. It is known that immature DCs have
decreased T cell activation ability due to the lack of co-stimulatory molecules but do produce more antigen-
presenting exosomes than mature DCs. Therefore, the transfer of exosomes from antigen-containing donor
DCs to recipient bystander DCs allows indirect antigen presentation and activation of T cells, especially
from the immature DCs, which are unable to successfully present the antigen on their own [51,59] .

Furthermore, the CD4+ and CD8+ T cells can also constitutively secrete exosomes containing TCR/CD3
[60]
complexes, which is enhanced upon TCR activation and can be either immune-activating or immune-
suppressing depending on the microenvironment. Activated T cells can transfer exosomes to induce
activation of resting T cells and enhance adaptive immune responses. For instance, CD3+ T cells activated
with IL-2 and anti-CD3-secreted exosomes promote the proliferation of CD8+ T cells as well as their
[61]
subsequent cytokine secretion .

Exosomes can also promote an immunosuppressed environment under certain circumstances. Exosomes
produced by immature DCs have been shown to induce T cell anergy/deletion as well as activate CD4+