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  • Review Article
  • Published:

Membrane vesicles as conveyors of immune responses

Nature Reviews Immunology volume 9, pages 581–593 (2009)Cite this article

Key Points

  • Secreted membrane vesicles are heterogeneous spherical structures that are limited by a lipid bilayer and contain cytoplasmic components from the donor cell. Secreted vesicles can be classified according to their intracellular origin: microvesicles, ectosomes and viruses are shed from the plasma membrane, whereas exosomes and exosome-like vesicles form in intracellular multivesicular compartments and are secreted following fusion of these compartments with the plasma membrane.

  • Membrane vesicles can be captured by neighbouring recipient cells through the interaction of vesicular ligands with cellular receptors (such as interactions between intracellular adhesion molecule 1 and lymphocyte function-associated antigen 1, phosphatidylserine and T cell immunoglobulin domain and mucin domain protein 4, as well as integrins and adhesion molecules). The precise mechanisms of interaction remain poorly characterized, but several studies suggest that vesicles can be internalized and might fuse with the recipient cell either at the plasma membrane or after internalization.

  • Exosomes and microvesicles contain transmembrane proteins, soluble cytoplasmic components and lipids, but also mRNAs and microRNAs derived from the donor cell. Recent in vitro studies show that mRNAs can be transferred to and transcribed in recipient cells, suggesting that secreted vesicles could modify the genetic profile of recipient cells.

  • Exosomes secreted by dendritic cells (DCs) bear functional preformed peptide–MHC complexes and can either directly activate antigen-specific effector T cells or transfer these complexes to recipient DCs to activate naive antigen-specific T cells. Material transferred by exosomes derived from all cell types (in particular tumours) can be processed and presented by recipient DCs.

  • Exosomes and microvesicles secreted by tumours have been shown to inhibit immune responses in an antigen-independent manner, especially by switching monocyte and T cell differentiation towards a tolerogenic phenotype. However, when injected with adjuvants or purified from stressed tumour cells, exosomes can induce potent antitumour responses.

  • Most studies described in this Review were carried out using vesicles purified in vitro from cultured cells or ex vivo from biological fluids. Membrane vesicles are secreted in vivo, but the demonstration of a function for this in vivo secretion will require the identification of tools to specifically inhibit their secretion.

  • Exosomes derived from DCs or tumours from patients with cancer have been used for immunotherapies, but clinical responses are limited. Future clinical trials will benefit from recent preclinical studies on exosomes and should involve a combination of exosomes and other immunomodulatory approaches.

Abstract

In multicellular organisms, communication between cells mainly involves the secretion of proteins that then bind to receptors on neighbouring cells. But another mode of intercellular communication — the release of membrane vesicles — has recently become the subject of increasing interest. Membrane vesicles are complex structures composed of a lipid bilayer that contains transmembrane proteins and encloses soluble hydrophilic components derived from the cytosol of the donor cell. These vesicles have been shown to affect the physiology of neighbouring recipient cells in various ways, from inducing intracellular signalling following binding to receptors to conferring new properties after the acquisition of new receptors, enzymes or even genetic material from the vesicles. This Review focuses on the role of membrane vesicles, in particular exosomes, in the communication between immune cells, and between tumour and immune cells.

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Figure 1: Different types of secreted membrane vesicles.
Figure 2: Protein composition of a canonical exosome.
Figure 3: Interaction of secreted membrane vesicles with recipient cells.
Figure 4: Involvement of secreted vesicles in interactions of immune cells.

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Acknowledgements

We acknowledge support from Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Institut National du Cancer, Fondation de France and European Research Council.

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  1. Institut National de la Santé et de la Recherche Médicale U932, Institut Curie, 26 Rue d'Ulm, Paris, 75005, France

    Clotilde Théry, Matias Ostrowski & Elodie Segura

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Glossary

Nibbling

The ability of dendritic cells to physically strip large membrane fragments from live cells on close contact without inducing death of the donor cell.

Trogocytosis

The transfer of plasma membrane fragments from one cell to another without cell death induction. This process is mediated by receptor signalling following cell–cell contact.

Nanotube

A membranous channel of 50–200 nm in diameter that connects cells over long distances.

Membrane vesicle

A spherical or approximately spherical structure limited by a lipid bilayer, which encloses soluble cargo.

MicroRNA

A small RNA molecule that regulates the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

Carrier vesicle

An intracellular membrane vesicle that buds from internal compartments (such as the endoplasmic reticulum, Golgi apparatus and endosomes) into the cytoplasm. Carrier vesicles contain cargo from the lumen of the donor compartment.

Follicular DC

A specialized non-haematopoietic stromal cell that resides in the follicles and germinal centres. Follicular dendritic cells (DCs) have long dendrites but are not related to DCs and carry intact antigen on their surface.

Regulatory T (TReg) cell

A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self tolerance, and a subset of these cells is characterized by expression of CD25 and the transcription factor forkhead box P3.

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Théry, C., Ostrowski, M. & Segura, E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9, 581–593 (2009). https://doi.org/10.1038/nri2567

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