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Donor dendritic cell–derived exosomes promote allograft-targeting immune response
Quan Liu, … , Adriana T. Larregina, Adrian E. Morelli
Quan Liu, … , Adriana T. Larregina, Adrian E. Morelli
Published August 1, 2016; First published June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):2805-2820. https://doi.org/10.1172/JCI84577.
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Categories: Research Article Transplantation

Donor dendritic cell–derived exosomes promote allograft-targeting immune response

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Abstract

The immune response against transplanted allografts is one of the most potent reactions mounted by the immune system. The acute rejection response has been attributed to donor dendritic cells (DCs), which migrate to recipient lymphoid tissues and directly activate alloreactive T cells against donor MHC molecules. Here, using a murine heart transplant model, we determined that only a small number of donor DCs reach lymphoid tissues and investigated how this limited population of donor DCs efficiently initiates the alloreactive T cell response that causes acute rejection. In our mouse model, efficient passage of donor MHC molecules to recipient conventional DCs (cDCs) was dependent on the transfer of extracellular vesicles (EVs) from donor DCs that migrated from the graft to lymphoid tissues. These EVs shared characteristics with exosomes and were internalized or remained attached to the recipient cDCs. Recipient cDCs that acquired exosomes became activated and triggered full activation of alloreactive T cells. Depletion of recipient cDCs after cardiac transplantation drastically decreased presentation of donor MHC molecules to directly alloreactive T cells and delayed graft rejection in mice. These findings support a key role for transfer of donor EVs in the generation of allograft-targeting immune responses and suggest that interrupting this process has potential to dampen the immune response to allografts.

Authors

Quan Liu, Darling M. Rojas-Canales, Sherrie J. Divito, William J. Shufesky, Donna Beer Stolz, Geza Erdos, Mara L.G. Sullivan, Gregory A. Gibson, Simon C. Watkins, Adriana T. Larregina, Adrian E. Morelli

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Figure 1

Transfer of donor MHC antigen in graft-draining lymphoid organs.

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Transfer of donor MHC antigen in graft-draining lymphoid organs.
(A) Mig...
(A) Migrating donor (BALB/c) DCs (IAd+) in T cell areas of the recipient (B6, H2b) spleen (arrows, insets). Confocal microscopy, original magnification, ×200. BALB/c cDCs (CD45.2+CD45.1–CD11c+) homed in the recipient (B6) spleen were undetectable by flow cytometry. Numbers indicate percentages of cells in the corresponding quadrant. Dot plots are representative of 1 untreated or recipient mouse of 3 per time point. (B) Quantities of donor cells mobilized from BALB/c heart grafts to the recipient (B6) spleens estimated by genomic PCR. Mean ± SD, 3 mice per variable. ND, not detected. (C) A donor DC (IAd hi, arrow) in the recipient spleen next to DCs expressing IAd dim or the IAb (B6)–IEα52–68 (BALB/c) complex (arrowheads, detected with the Yae Ab) that likely corresponded to recipient DCs that acquired donor IAd or donor IEα52–68 peptide, respectively. Confocal microscopy, original magnification, ×200. (D) FACS analysis of numbers of recipient (B6) splenic APCs with donor H2Kd or IAd molecules at successive PODs after transplantation of BALB/c hearts. Mean ± SD, 3 mice per variable. P values were generated by 1-way ANOVA followed by Tukey-Kramer multiple comparisons test.
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