Date: Saturday, May 30, 2020
Session Name: Antigen Presentation / Allorecognition / Dendritic Cells
Session Time: 3:15pm-4:45pm
Presentation Time: 4:27pm-4:39pm
*Purpose: The precise mechanisms of liver transplant tolerance are yet to be elucidated. Non-conventional plasmacytoid dendritic cells (pDCs) are thought to promote immune regulation, including oral tolerance and heart allograft acceptance, in animal models. They are comparatively numerous in the mouse liver compared with secondary lymphoid tissue. However, the role of donor interstitial liver pDCs in liver transplantation remains unclear. Our aim was to assess the influence of donor liver pDC on the induction of liver transplantation tolerance in a fully MHC-mismatched mouse model
*Methods: We determined the phenotype and function of pDCs and T cells by qRT-PCR, flow cytometric analysis and CFSE-MLR, and performed orthotopic liver transplantation from B6 (H2b) donors to C3H (H2k) recipients (Nature Protocols 2016; 11:1163), without immunosuppressive therapy.
*Results: Liver pDCs expressed higher levels of the transmembrane adaptor DNAX-activating protein of 12kDa (DAP12) and its co-receptor triggering receptor expressed on myeloid cells 2 (TREM2) and a higher PD-L1/CD86 ratio, both in the steady-state and following TLR9 stimulation compared with spleen pDCs (p<0.05). Moreover, liver pDCs demonstrated inferior ability to stimulate allogeneic T cell proliferation compared with spleen pDCs (p<0.05). When untreated or pDC-depleted B6 donor livers were transplanted into normal C3H recipients, mice given pDC-depleted livers showed significantly poorer graft survival (median survival time 25 days) compared to those given untreated donor livers that survived >100 days (p<0.05). pDC-depleted allografts expressed significant higher granzyme B and perforin levels, and lower co-inhibitory PD-L1 levels compared with untreated allografts 4 days after transplantation (p<0.05). In addition, the proportion of CD25+FoxP3+ Treg in grafts and mesenteric lymph nodes of mice given pDC-depleted livers was reduced significantly compared with controls (p<0.05). Furthermore, CD8+T cells infiltrating the grafts, and in spleen and lymph nodes of the untreated donor group exhibited an exhausted phenotype (PD-1+, TIM-3+), compared with the pDC-depleted donor group (p<0.05).
*Conclusions: These novel observations suggest that liver interstitial pDCs play a key immunoregulatory role in mouse liver transplant tolerance and also suggest investigation of their therapeutic potential as cellular therapeutic agents in organ transplantation.
To cite this abstract in AMA style:Nakano R, Yoshida O, Kimura S, Geller D, Thomson A. Liver Plasmacytoid Dendritic Cells Express High Levels of DAP12, TREM2 and PD-L1 and Promote Effector T Cell Exhaustion and Augmented Treg Responses in Spontaneous Liver Transplant Tolerance [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/liver-plasmacytoid-dendritic-cells-express-high-levels-of-dap12-trem2-and-pd-l1-and-promote-effector-t-cell-exhaustion-and-augmented-treg-responses-in-spontaneous-liver-transplant-tolerance/. Accessed October 26, 2020.
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