The immune system generates a powerful response against transplanted organs that rapidly promotes rejection of the allograft in the absence of immunosuppressive therapies. This response has been linked to donor dendritic cells (DCs) that migrate from the graft into host lymphoid tissue, where they can activate alloreactive T cells that target donor MHC molecules. Quan Liu and colleagues at the University of Pittsburgh used a murine heart transplant model and determined that only a very small number of donor-derived DCs reach host lymphoid tissues. The graft-derived DCs that did reach the lymphoid tissue transferred donor MHC-containing extracellular vesicles (EVs) to recipient conventional DCs (cDCs). The EVs were characteristic of exosomes and remained attached to or were internalized by recipient cDCs. EV uptake activated recipient DCs, which then directly induced alloreactive T cells by presenting donor MHC peptides. Importantly, depletion of recipient cDCs after transplantation substantially delayed allograft rejection. The results of this study reveal the contribution of DC-derived EVs in allograft rejection and suggest that targeting EV-mediated transfer of donor MHC molecules has potential to promote allograft tolerance. The accompanying image shows a time-lapse analysis of the transfer of RFP-labeled EVs (red) from a donor-derived DC (blue) to recipient cDC (green).
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.
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