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Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition¹

Angela Montecalvo^*,, William J. Shufesky^*,, Donna Beer Stolz, Mara G. Sullivan, Zhiliang Wang^*,, Sherrie J. Divito^*,, Glenn D. Papworth, Simon C. Watkins, Paul D. Robbins, Adriana T. Larregina^¶,|| and Adrian E. Morelli^2,*,,||

^* Thomas E. Starzl Transplantation Institute, Department of Surgery, Department of Cell Biology, Department of Molecular Genetics and Biochemistry, ^¶ Department of Dermatology, and ^|| Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213

Exosomes are nanovesicles released by different cell types including dendritic cells (DCs). The fact that exosomes express surface MHC-peptide complexes suggests that they could function as Ag-presenting vesicles or as vehicles to spread allogeneic Ags for priming of anti-donor T cells during elicitation of graft rejection or induction/maintenance of transplant tolerance. We demonstrate that circulating exosomes transporting alloantigens are captured by splenic DCs of different lineages. Internalization of host-derived exosomes transporting allopeptides by splenic DCs leads to activation of anti-donor CD4 T cells by the indirect pathway of allorecognition, a phenomenon that requires DC-derived, instead of exosome-derived, MHC class II molecules. By contrast, allogeneic exosomes are unable to stimulate direct-pathway T cells in vivo. We demonstrate in mice that although graft-infiltrating leukocytes release exosomes ex vivo, they do not secrete enough concentrations of exosomes into circulation to stimulate donor-reactive T cells in secondary lymphoid organs. Instead, our findings indicate that migrating DCs (generated in vitro or isolated from allografts), once they home in the spleen, they transfer exosomes expressing the reporter marker GFP to spleen-resident DCs. Our results suggest that exchange of exosomes between DCs in lymphoid organs might constitute a potential mechanism by which passenger leukocytes transfer alloantigens to recipient’s APCs and amplify generation of donor-reactive T cells following transplantation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 HL075512 and HL077545 (to A.E.M.), and R01 CA100893 (A.T.L.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Adrian E. Morelli, Department of Surgery, W1556 Biomedical Science Tower, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213-2582. E-mail address: morelli{at}imap.pitt.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; GIDC, graft-infiltrating DC; GIL, graft-infiltrating leukocyte; MVB, multivesicular body; RAd, recombinant adenovirus; eGFP, enhanced GFP; FasL, Fas ligand; LAMP, lysosomal-associated membrane protein; MFG-E8, milk fat globule-E8; WT, wild type.