Biological effects of exosomes

The primary aim of exosomal release for a cell might be to discard membrane proteins. This role was suggested for reticulocyte-derived exosomes that carry transferring receptors (TfRs) useless in erythrocytes (36). Thus, exosomes could be an alternative to lysosomal degradation, for example, to eliminate proteins that resist degradation by lysosomal proteases.

However, based on their protein composition, i.e., enrichment for MHC complexes, hsp, and some targeting molecules, it is conceivable that exosomes and more specially APC-derived exosomes might be involved in amplification of antigen presentation. Raposo and colleagues (33) first observed that MHC class II molecules borne on Epstein-Barr virus (EBV)-transformed B-lymphocyte-derived exosomes were functional when associated with antigenic peptides. These exosomes could induce significant but weak MHC class II-restricted-CD4+ T-cell proliferation in vitro. We further demonstrated that the MHC class I/peptide complexes harbored by mouse and human DC-derived exosomes are functional to trigger peptide-specific, MHC class I-restricted T-cell clones and to elicit primary Tc1 lymphocyte responses in vitro and in vivo. However, exosome-mediated T-cell responses require DC in vitro and in vivo for both CD4+ and CD8+ T-cell priming (29-31). Moreover, tumor peptide-pulsed DC-derived exosomes induce tumor growth retardation of established murine tumors in a T-cell-dependent manner (5).

In addition to transferring preprocessed antigens in MHC molecules, exosomes might also transfer hsp-associated peptides or cytosolic whole candidate tumor antigens. We could demonstrate that melanoma cells release exosomes containing whole tumor proteins such as MART-1/melanA. Following DC uptake of such melanoma-derived exosomes, cross-presentation of MART-1 peptides by DC MHC class I molecules could be observed. In vivo, DCs pulsed with texosomes induced potent CD8+ T-cell-dependent antitumor effects against established mouse tumors (6).

The relevance of exosome secretion by an immature DC remains questionable. Since exosomes are specifically enriched with functional MHC complexes and bear targeting molecules for DCs or other APCs, and since exosome uptake by recipient DCs appears rapidly saturated (our unpublished data), it is tempting to speculate that secretion of exosomes by DCs is an amplification pathway for the antigen presentation network, enabling rapid dissemination of processed MHC complexes for T-cell stimulation. As suggested for the immunological synapse and for the tetraspan-enriched domains (37), the presence of exosomes on the membrane of immature DCs might trigger sustained engagement of T-cell receptors. One could postulate that exosome secretion might occur in the lymph or in the T-cell area of lymphoid organs.

Likewise, it is also conceivable that exosomes are involved in peripheral tolerance and inhibition of immune responses. Experiments in rats reported that intraperitoneal injections of exosomes derived from a gut epithelial cell line loaded with Ag led to a decrease of the Ag specific delayed-type hypersensitivity reaction (38). Moreover, in allogeneic cardiac transplantation models, Cuturi and colleagues showed that donor LEW.1W DC exosomes injected intravenously induce LEW.1W heart allograft tolerance in LEW.1A rat recipients. Prophylactic usage of exosomes in recipients was more efficient in prolonging allograft survival than therapeutic usage (39). Finally, recent studies showed that T cells can acquire peptide/MHC class II complexes from APCs (10,13). These T lymphocytes were killed by neighboring lymphocytes, suggesting that fratricidial T-cell killing could represent a negative feedback loop of immune responses (40). The role of exosomes in such a membrane exchange has not been investigated.

All reported studies dealing with exosome functions utilized exosomes from culture supernatants of propagated cell lines. Exosomes have been observed in vivo for the first time in electron microscopy studies of human follicular DCs (FDCs) in tonsils (2). Forty-to 70-nm microvesicles expressing tetraspanins have been observed in situ on the plasma membrane of FDCs. They also expressed MHC class II molecules that are not neo-synthesized by FDCs. These vesicles contained lysobiphosphatidic acids, a lipid found on the luminal vesicles of MVBs. The possibility that these vesicles could be iccosomes, i.e., interconnected immune complex-coated body (antigen-antibody complexes) was excluded on the basis of their size (0.3-0.7 ^m) and composition (flocculent peroxidase-positive material). The authors hypothetized that these microvesicles were exosomes originating from germinal center B lymphocytes or neighboring DCs.

We recently reported that high amounts of tumor exosomes accumulate in the malignant effusions of patients bearing different types of tumors (melanoma, breast, lung, ovarian cancer, mesothelioma) (4). Exosomes harvested from ascitis of melanoma patients efficiently transport MART-1 tumor antigen to monocyte-derived dendritic cells (MD-DCs) for cross-presentation to MART-1-specific CTL clones. Moreover, in in vitro stimulation assays aimed at priming peripheral CD8+ T lymphocytes using autologous DCs, ascitis-derived exosomes could prime naive T cells recognizing the autologous primary tumor culture in an MHC class I-restricted manner in seven out of nine cancer patients. Whether exosomes produced in vivo mediate any immune functions remains hypothetical. The poor immunogenicity of texasomes in vivo might be a result of the absence of myeloid DCs and/or the presence of immunosuppressive agents (i.e., IL-10 and transforming growth factor-P [TGF-P]) in ascitis.

Altogether, these data suggest that exosomes constitute a novel pathway of antigen transfer-modulating T-cell activation, and that such antigen-presenting vesicles could be suitable for cancer immunotherapy. The mechanisms of their in vivo functions and their relevance remain to be established.

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