Exosomes: composition, biogenesis and function

Key Points

  • Exosomes are saucer-shaped vesicles of 30–100 nm in diameter, which are delimited by a lipid bi-layer and which float at a density of 1.13–1.19 g ml−1 in sucrose gradients. These vesicles are secreted by various cells in culture.

  • Analysis of the protein composition of exosomes that are secreted by various cells reveals the presence of some common proteins, which define exosomes as a bona fide secreted subcellular compartment, as well as the presence of some cell-type-specific proteins, which could mediate the different functions of exosomes that are produced by different cell types.

  • All of the proteins that have been identified in exosomes are localized in the cell cytosol or endosomal compartments, never in the endoplasmic reticulum, Golgi apparatus, mitochondria or nucleus. Exosomes also contain some plasma-membrane proteins, which have been described also in endosomal compartments. These observations are consistent with the proposed origin of exosomes as internal vesicles of late multivesicular compartments.

  • Formation of the internal vesicles of multivesicular bodies by inward budding from the limiting membrane involves a budding event of inverse membrane orientation compared with the classical intracellular budding events that take place in a cell. All inverse budding events seem to be correlated with an inversion of the transmembrane partition of the lipid phosphatidylserine.

  • Membrane exchanges between cells have been described during the interactions of T cells and antigen-presenting cells (from the T cell to the antigen-presenting cell, or reciprocally, depending on the analyses), or between dendritic cells. It is not clear whether such exchanges involve exosomes.

  • The biological functions of exosomes remain unclear. The original role of exosomes was most probably to eliminate undegraded endosomal or lysosomal proteins and membranes. Recent results indicate, however, that in different cell types, exosomes might have other functions, such as the stimulation or inactivation of T cells, or the transfer of antigens to dendritic cells.

  • Regardless of their putative physiological functions, exosomes have been used successfully in preclinical mouse and human tumour immunotherapy assays. A Phase I clinical trial in melanoma patients is ongoing.

Abstract

Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture. Interest in exosomes has intensified after their recent description in antigen-presenting cells and the observation that they can stimulate immune responses in vivo. In the past few years, several groups have reported the secretion of exosomes by various cell types, and have discussed their potential biological functions. Here, we describe the physical properties that define exosomes as a specific population of secreted vesicles, we summarize their biological effects, particularly on the immune system, and we discuss the potential roles that secreted vesicles could have as intercellular messengers.

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Figure 1: Summary of the observations that led to the first description of exosomes.
Figure 2: Schematic representation of exosomes produced by dendritic cells.
Figure 3: Orientation of various budding events occuring in a cell.
Figure 4: Working model for the role of exosomes in immune responses.

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Acknowledgements

We thank C. Hivroz and P. Benaroch for helpful comments on the manuscript. S.A. and L.Z. were supported by European Community grants.

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Correspondence to Clotilde Théry.

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DATABASES

Entrez

EBV

LocusLink

A33

αM

annexin I

annexin II

annexin IV

annexin V

annexin VI

APO2L/TRAIL

β2

CBL

CCR5

CD3

CD9

CD13

CD26

CD28

CD37

CD40L

CD45

CD53

CD59

CD63

CD74

CD81

CD82

CD86

CDC25

cofilin

enolase-1

FASL

HLA-DM

HSC70

HSP70

HSP90

ICAM1

IFN-γ

IL-2

LAMP1

LAMP2

LCK

MAGE3

MART1

MFGE8

NSF

P-selectin

RAB5

RAB7

RAP1B

SNAP

SNAP23

synaptotagmin II

synaptotagmin VII

syntaxin-3

syntaxin-4

TSG101

VAMP7

VAMP8

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Glossary

ANNEXINS

A family of cytosolic proteins that have phospholipid-binding domains, the association of which with intracellular membranes is regulated by Ca2+. Several annexins are involved in membrane-fusion events between intracellular compartments.

RAB PROTEINS

Cytosolic proteins that have GTPase activity, which, in their GTP-bound form, associate with membranes. Different RAB proteins associate with different intracellular compartments — for example, RAB5 associates with early endosomes, RAB7 with late endosomes and RAB11 with recycling endosomes.

HEAT-SHOCK PROTEINS

(HSPs). A family of proteins that are involved in the binding of other misfolded proteins, and transporting them to the cellular degradation machinery. Several HSPs are synthesized only in conditions of stress, such as heat shock, but a few family members — such as endoplasmic-reticulum-resident gp96, and cytosolic HSC70 and HSP84 — are expressed constitutively.

TETRASPANINS

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes, which are defined by several conserved amino acids in the transmembrane domains. Their function is not known clearly, but they seem to interact with many other transmembrane proteins and to form large multimeric protein networks.

DEGRANULATION

In mastocytes and cytotoxic T lymphocytes, this term refers to the activation-induced fusion of secretory granules with the plasma membrane, and to the subsequent release of the content of these granules into the extracellular space.

FOLLICULAR DENDRITIC CELLS

(FDCs). Cells with a dendritic morphology that are present in the lymph nodes, where they present intact antigens held in immune complexes to B cells. FDCs are of non-haematopoietic origin, and are not related to dendritic cells.

CROSS-PRESENTATION

This term refers to the ability of certain antigen-presenting cells (APCs) to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, as most cells present exclusively peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses against viruses that do not infect APCs.

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Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2, 569–579 (2002). https://doi.org/10.1038/nri855

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