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  • Review Article
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Regulation of immune responses by extracellular vesicles

Key Points

  • Extracellular vesicles, including exosomes, are small membrane vesicles that are derived from multivesicular bodies or that bud from the plasma membrane. Most, if not all, cell types release extracellular vesicles that then enter almost all bodily fluids.

  • Extracellular vesicles, which carry proteins, lipids, mRNAs and non-coding RNAs including microRNAs, have important roles in intercellular communication, both locally and systemically, by transferring their contents between cells.

  • Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune cells, such as stem cells, and immune cells participate in immune regulation. As a result of the immunoregulatory activity of extracellular vesicles, therapeutic approaches using these vesicles are being developed and clinically tested for the treatment of inflammatory and autoimmune diseases and cancer.

  • Extracellular vesicles that carry tumour or pathogenic peptides presented by MHC class I and MHC class II complexes can stimulate CD4+ and CD8+ T cells directly as well as indirectly through an interaction with antigen-presenting cells (APCs). Peptide–MHC complexes of extracellular vesicles that become attached or fused to APC surfaces might also be directly presented to T cells without the need for peptide–MHC complex reprocessing through a mechanism known as cross-dressing.

  • Extracellular vesicles can be immunostimulatory through the transfer of both antigens and signals to APCs to promote their activation into immunogenic APCs. By contrast, certain extracellular vesicles can render APCs immunosuppressive through multiple mechanisms, which results in the induction of regulatory T cells.

  • The immunoregulatory activity of tumour-derived and APC-derived extracellular vesicles can be enhanced by treatment of the parental cells with cytokines, by stress (such as heat shock) or by gene transfer of immunoregulatory factors such as CD95 ligand, indoleamine 2,3-dioxygenase or interleukin-4.

Abstract

Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle-based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications.

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Figure 1: Biogenesis of extracellular vesicles.
Figure 2: Role of extracellular vesicles in antigen presentation.
Figure 3: Role of extracellular vesicles in regulating tumour and microorganism immunity that can be modified for therapeutic applications.
Figure 4: Mechanism of transfer of exosomal shuttle RNAs between cells.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants AG024827, AG033907, AR051456, AR055373 and AG043376 to P.D.R. and HL075512 and HL077545 to A.E.M.

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Correspondence to Paul D. Robbins or Adrian E. Morelli.

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Therapeutic applications of extracellular vesicles (PDF 658 kb)

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Glossary

microRNAs

(miRNAs). Small non-coding RNAs (22 nucleotides in length) that post-transcriptionally regulate gene expression by binding to seed sequences on target mRNAs, which results in mRNA degradation or inhibition of mRNA translation.

Tetraspanin

An evolutionarily conserved four transmembrane domain protein that associates with other tetraspanins, integrins, MHC molecules or signalling receptors in tetraspanin-enriched domains, and this leads to the regulation of multiple cell functions including cell adhesion, morphogenesis, proliferation, differentiation, synapse formation and tumour invasion.

Cross-dressing

The passage of intact preformed peptide–MHC class I or MHC class II complexes from a donor cell to the surface membrane of an acceptor antigen-presenting cell or another type of target cell. The transferred peptide–MHC complexes are recognized by T cells without the need of further antigen processing.

Cross-presentation

The transfer of biosynthesized antigen in a complex form (for example, as apoptotic cell fragments or associated with heat shock protein) from donor (infected or tumour) cells to the cytosol of acceptor antigen-presenting cells for processing and presentation through MHC class I molecules to CD8+ T cells. In certain cases, the acquired antigen can be presented by MHC class I molecules through a transporter associated with antigen processing (TAP)-independent mechanism that involves delivery of the antigen to MHC class I-containing phagolysosomes.

Iccosomes

Membrane vesicles (0.25–0.38 μm in diameter) that are pinched off from the delicate processes of follicular dendritic cells. Iccosomes carry immune complexes with native antigens and C3-derived complement fragments on the surface, which activate B cells. During B cell activation, iccosomes are recognized and internalized by follicular B cells in an antigen-specific manner.

Delayed-type hypersensitivity response

(DTH response). A CD4+ T cell-driven, antigen-specific immune response that is induced by intradermal antigen immunization followed by injection of the antigen in the skin of the ear or the footpad. The immune response is measured by swelling and redness.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of leukocytes of myeloid lineage that increase in number during cancer and inflammation and that suppress T cell responses. They include myeloid progenitor cells, immature macrophages, granulocytes and dendritic cells.

Mesenchymal stem cells

(MSCs). Multipotent stromal cells that can differentiate into a variety of cell types that are derived from the mesoderm including osteoblasts, chondrocytes and adipocytes, but not into haematopoietic cells.

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Robbins, P., Morelli, A. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14, 195–208 (2014). https://doi.org/10.1038/nri3622

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