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Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27 Page 3 of 20

secretion, adhesion molecule expression, tissue factor release, and leukocyte recruitment [16,17] . Furthermore,
the upregulation of adhesion molecules and chemokines by activated ECs also serves to selectively recruit
[18]
specific T cell types in circulation . During this recruitment, antigen presentation may occur between the
ECs and T cells mediated by major histocompatibility complex (MHC). It is known that ECs express MHC
[14]
Class I on their surface, as well as MHC Class II in certain vasculatures of the body . Due to this presence
of MHC, ECs can act as antigen-presenting cells (APCs) to present antigen to effector or memory T cells .
[19]
Interaction with T cell co-stimulatory or co-inhibitory molecules expressed on ECs, such as CD80, CD86,
LFA-3, ICOS-L, PDL-1, CD40, and CD134L, also mediates the T cell response .
[14]

Due to their ability to act as APCs, ECs may generate certain T cell subsets to induce either inflammation
[14]
or immune tolerance . For instance, it has been shown that ECs support T cell proliferation and increases
[20]
in the number of suppressor Treg cells and can stimulate the production of pro-inflammatory Th17
[21]
cells under inflammatory conditions . ECs are also directly recognized by effector memory CD4+ T cells
to stimulate IFN-g production and subsequent CD4+ Th1 polarization . This phenomenon has been
[22]
further supported by a study involving activation of the ECs mediated by the C3a and C5a anaphylatoxins,
which induce a Th1 phenotype, an increase in IFN-g production, and activation of B lymphoblasts .
[23]
Taken together, the evidence suggests that VE plays a critical role in the initial onset of inflammation,
innate immunity, and subsequent adaptive immunity in response to diverse stimuli present within the
bloodstream.

Exosomes
Exosomes are membrane-bound extracellular vesicles between 40 and 100 nm in diameter that have been
[24]
recognized as important players in cell-to-cell signaling . They are secreted into the extracellular space
by ECs and various other cells, such as platelets, immunocytes, and smooth muscle cells [25-27] and are
[28]
present in almost all biological fluids . Extracellular exchange of exosomes containing various bioactive
molecules takes place continuously between organelles to foster communication during homeostasis and
[29]
diseased states . Exosome production begins with the internalization of the cellular membrane through
endocytosis to form an endosome, followed by the invagination of the endosomal membrane, which
matures into multivesicular bodies (MVBs). The MVBs can then either be degraded by internal lysosomes
or are transported to the cell membrane to undergo transcytosis or fusion and release of the contained
liberates intraluminal vesicles into the extracellular space, becoming exosomes [28,30] . Contents carried
by exosomes consist of different proteins, lipids, metabolites, RNA, and DNA, which may be exchanged
between the exosomes and their target cells.

Originally, exosomes were thought to be involved only in the process of excretion of unnecessary/unwanted
proteins, and several studies have revealed that cellular stress triggers an enhanced release of exosomes [31-34] .
However, further studies have suggested the participation of exosomes in cellular communication
associated with many physiological and pathological states due to their ability to influence the phenotype
of recipient cells [24,28] . Exosomes can target cells through specific receptor binding to activate cell-to-cell
signaling pathways, which induce specific functions . Information from an exosome may be transferred
[35]
[36]
to the recipient cell either by interacting at the cell surface or by endosomal uptake . Functions of released
exosomes include horizontal gene transfer, inflammation, antigen presentation, tumor progression, and
mediation of the immune response during pathogenic states [35,37] .

Exosomes have been isolated from protozoa, bacteria, viruses, and fungi but each has distinct exosome
[38]
profiles with varying compositions . Protozoan parasites modulate host cells by producing exosomes
containing virulence factors and effector molecules. In this way, parasites can manipulate host gene
[39]
expression, immune responses, and other factors that favor parasite growth, survival, and pathogenesis .
Exosomes released during infection may also facilitate host immunity [38,40] .