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

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

Research output: Contribution to journalReview article

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2805-2820
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number8
DOIs
Publication statusPublished - 1 Aug 2016
Externally publishedYes

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    Liu, Q., Rojas-Canales, D. M., Divito, S. J., Shufesky, W. J., Stolz, D. B., Erdos, G., Sullivan, M. L. G., Gibson, G. A., Watkins, S. C., Larregina, A. T., & Morelli, A. E. (2016). Donor dendritic cell-derived exosomes promote allograft-targeting immune response. Journal of Clinical Investigation, 126(8), 2805-2820. https://doi.org/10.1172/JCI84577