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 June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):2805-2820. https://doi.org/10.1172/JCI84577.
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Research Article Transplantation

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

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 10

Recipient cDCs present donor MHC molecules to directly alloreactive T cells after heart transplantation.

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Recipient cDCs present donor MHC molecules to directly alloreactive T ce...
(A) Survival of BALB/c cardiac grafts in CD11c-DTR-B6 BM chimeras depleted of recipient cDCs. Recipient numbers are in parentheses. (B) Quantification by immunofluorescence microscopy of donor (BALB/c) cDCs (CD11c+IAd+) on tissue sections of spleens of B6 (H2b) recipients, on successive PODs. Results represent the analysis of 10 panoramic sections of each spleen per POD and animal group. Results were analyzed with 1-way ANOVA followed by Tukey-Kramer multiple comparisons test. Cells were counted with MetaMorph Offline 7.7.50 software. NS, not significant; ND, not detected. (C) Top: Donor (BALB/c) cDCs detected on tissue sections of spleens from DT-treated WT B6 BM chimeras (control) and DT-injected CD11c-DTR BM chimeras were identified by expression of IAd hi (green) and CD11c (red). Bottom: Homing of donor (BALB/c, IAd+) cDCs (green) to splenic T cell areas (red) in DT-treated WT B6 BM chimeras (control) and DT-injected CD11c-DTR BM chimeras. Arrows indicate the donor DCs shown in detail in the insets. Nuclei were stained blue with DAPI. Immunofluorescence microscopy, original magnification, ×400. Sections are representative of 3 animals per variable. (D) Enzyme-linked ImmunoSpot (ELISPOT) analysis of the recipient T cell response against donor MHC molecules (direct pathway) or donor-derived peptides presented by recipient MHC molecules (indirect pathway) in the spleen on POD 7. Results were pooled from 3–4 mice per group. P values were generated by 1-way ANOVA followed by Tukey-Kramer multiple comparisons test. (E) Anti-donor (BALB/c) Ab titers in serum on POD 7. Recipient numbers are in parentheses.