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Review
. 2013 Jan;251(1):125-42.
doi: 10.1111/imr.12013.

Transfer of extracellular vesicles during immune cell-cell interactions

Cristina Gutiérrez-Vázquez  1 , Carolina Villarroya-Beltri, María Mittelbrunn, Francisco Sánchez-Madrid
Affiliations
Review

Transfer of extracellular vesicles during immune cell-cell interactions

Cristina Gutiérrez-Vázquez et al. Immunol Rev. 2013 Jan.

Abstract

The transfer of molecules between cells during cognate immune cell interactions has been reported, and recently a novel mechanism of transfer of proteins and genetic material such as small RNA between T cells and antigen-presenting cells (APCs) has been described, involving exchange of extracellular vesicles (EVs) during the formation of the immunological synapse (IS). EVs, a term that encompasses exosomes and microvesicles, has been implicated in cell-cell communication during immune responses associated with tumors, pathogens, allergies, and autoimmune diseases. This review focuses on EV transfer as a mechanism for the exchange of molecules during immune cell-cell interactions.

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Figures

Figure 1
Figure 1. Typical molecular composition of T-cell exosomes
Membrane and luminal distribution of molecules predicted to be found in a typical exosome produced by a T lymphocyte. TCR: T-cell receptor; TGFβ: transforming growth factor beta; ICAMs: intercellular adhesion molecule family; CXCR4: C-X-C chemokine receptor type 4 or CD184; Tsg101: tumor susceptibility gene 101; TRAIL: TNF-related apoptosis-inducing ligand; FasL: Fas ligand or CD95L; TfR: transferrin receptor; Mfge8: milk-fat globule-EGF factor 8; ALIX: ALG-2-interacting protein X; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; ERMs: ezrin, radixin and moesin proteins. For more information about exosome composition see http://www.exocarta.org.
Figure 2
Figure 2. Role of immune-cell-derived EVs during infection
During infection dendritic cells (DC) produce EVs that carry co-stimulatory molecules, antigens and Ag-MHC-II complexes. These EVs transfer Ag-presentation ability to other DCs and also to B cells and T cells (79, 82, 83), and might directly activate T cells (81, 83). Mast cells and macrophages can also transfer Ag-containing EVs to DCs and induce maturation and presentation of the acquired Ags (102, 152). EVs from macrophages also activate innate immune responses in uninfected macrophages (217). During Ag presentation, TCR and BCR triggering stimulate EV secretion (61, 70), and the formation of a functional immune synapse promotes the functional transfer of EVs (6). Activated T cells produce immune-regulatory EVs that inhibit NK cytotoxicity (65), promote apoptosis in T cells (38) and Ag-carrying DCs (64), and decrease DC antigen-presentation ability (64), thus contributing to homeostasis recovery.
Figure 3
Figure 3. Tumor-derived EVs promote tumor growth via multiple routes
Tumor-derived EVs suppress anti-tumor immune responses by inhibiting T-cell activation and proliferation and stimulating their apoptosis (34, 41, 114-117, 119). EVs produced by tumor cells also induce regulatory T cells and MDSCs (34, 118, 120, 121, 130) and inhibit the cytotoxicity of NK and CD8+ T cells (34, 122-125). Tumor-derived EVs are taken up by endothelial cells promoting angiogenesis and tumor invasion; the expression of CD147, D6.1A, tissue factor and EGFR in EVs, the transfer of pro-angiogenic components and the induction of MMPs play a role in the pro-angiogenic effects of tumor EVs (52, 132, 134-137). Tumor EVs also contribute to tumor growth by stimulating tumor proliferation and inducing metastatic behavior in bone-marrow progenitors (52, 138, 139).
Figure 4
Figure 4. Mechanisms of protein and genetic-material exchange during immune-cell contacts
A: Trogocytosis consists of the rapid transfer of membrane patches, allowing exchange of intact membrane proteins (180). Transfer of intact membrane proteins between cells is also mediated by trans-endocytosis of membranous material (192). Membrane bridges can be formed between cells, connecting their cytoplasms (170). B: Nanotubes are tubular membranous connections between cells that are either limited to the exchange of membranes between cells or also allow communication between the two cytoplasms (218). C: EVs are exchanged during IS formation. It is possible that MVB-derived exosomes are delivered directionally at the IS, while other EVs are delivered adirectionally into the extracellular space near the recipient cell. D: Gap junctions are composed of connexin proteins that form a channel directly connecting the cytoplasms of two cells, allowing the transfer of material. It is also possible that gap junctions formed at the IS discharge material into the intercellular space between the two cells.
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