Current Immunology Reviews, 2005, 1, 1-6 1 Exosomes: Specific Intercellular Nano-Shuttles? Ana Maria Barral and Matthias G. von Herrath * Division of Developmental Immunology. La Jolla Institute for Allergy and Immunology, 10355 Science Center drive, San Diego, CA, 92121, USA Abstract: The term “exosome” was coined in 1981 (Trams et al, Biochim Biophys Acta , 1981, 645:63) when the presence of “exfoliated membrane vesicles with 5’-nucleotidase activity” was first reported. Since then, in the biomedical literature the term exosome has evolved to designate both the above mentioned small vesicles of endocytic origin and the 3’->5’ exonuclease complex involved in RNA processing and degradation. In the present review we will focus on the original definition of exosomes and particularly on their emerging role as intercellular signaling devices. Exosomes are secreted by a variety of cells, particularly antigen-presenting cells such as DCs, B cells and macrophages. Enriched in MHC class I and II antigens and costimulatory molecules, they are considered to be an alternative pathway of antigen delivery and presentation. The use of exosomes engineered to prime the immune system against tumor antigens is a promising new arm of cancer immunotherapy. On the other hand, exosomes released by the tumor itself may provoke a tolerogenic response. Participation of exosomes in other immune mechanisms, such as platelet activation, mast cell degranulation, germinal center reaction and engulfment of apoptotic cells has also been postulated. An evolutionary link between retroviruses and exosomes has recently been proposed. In general, viruses can use the host’s intracellular machinery for their budding, and exosomes may constitute a vehicle for transmission of pathogens and interaction with the immune system. A deeper knowledge of the cells targeted by exosomes and the mechanisms governing these interactions will give a clear picture of the role of exosomes as intercellular messengers. Keywords: Exosomes, antigenic presentation, multivesicular bodies, endosomes, LCMV. INTRODUCTION malignant effusions [13, 14] and bronchoalveolar lavage fluid [10, 15]. Advanced proteomic analysis would reveal not only a set of molecules common to all exosomes, but also cell type-specific differences. The latter, of course, is related to the different functions of exosomes- functions that seem straightforward on occasions. Here we can include the previously mentioned transferrin receptor disposal by differentiating reticulocytes [1, 16-20] or the provision of MHC class II antigens to follicular DCs by B-cell produced exosomes [21]. In most of the cases, however, many questions remain. What is the in vivo relevance of exosomes in antigen presentation and T-cell priming? Is the concentration of antigenic peptides, MHC antigens and costimulatory molecules high enough in vivo to achieve a significant response? Is it a true “long-distance” mechanism capable of transferring the antigenic stimulation from an antigen-presenting cell (APC) to a distant T-cell? Or are exosomes only metabolic by-products of signaling events occurring on the cell surface (particularly lipid rafts), which must be shed and disposed of by other cells [22]? Many scientists are still skeptical about exosomes. Indeed, these elusive nano-structures seem to provoke the same reaction as their “cousins”, lipid rafts or caveolae did some years ago. Although described for the first time in the early 80s, exosomes have been relegated to the obscure group of “bubbles” that shuttle molecules between intracellular compartments, of interest only to zealous cell biologists passionate about “trafficking” issues. Neither exosomes’ well-studied role in transferrin receptor disposal during reticulocyte differentiation [1] nor anecdotic reports of exosome-like particle release in semen [2] and mast cells [3] gave them enough recognition. They emerged though to the spotlight after studies appeared describing B and dendritic cell (DC)-derived exosomes as tiny antigen-presenting machineries, capable of stimulate T-cells [4, 5]. Moreover, exosomes loaded with tumor peptides can elicit potent anti-tumor responses, a fact being presently tested in clinical trials. In this review we intend to focus on exosomes as part of a dynamic intra and intercellular transport system. At the intracellular level exosomes are still parts of multivesicular bodies (MVBs) and constitute an integral part of the endosomal system, involved in the transport, recycling or degradation of molecules. If released into the extracellular milieu, however, exosomes seem to act as messengers delivering specific molecules to target cells. At this level they can be used for clinical purposes, either purified from the organism or artificially synthesized. Particular emphasis will be placed on the crossroad of viral propagation and Suddenly, everybody was looking for exosomes: and they seem to be everywhere. Not only immune cells such as DCs, B cells and mast cells, but also platelets, tumor cells, renal and prostatic epithelial cells produce exosomes (for excellent reviews, see [6-9]). Exosomes were detected in biological fluids such as serum [10, 11], urine [12], *Address correspondence to this author at the La Jolla Institute for Allergy and Immunology, 10355 Science Center drive, San Diego, CA, 92121, USA; Tel: (858) 558 3571; Fax: (858) 558 3579; E-mail: matthias@liai.org 1573-3955/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.