Background: The mechanism underlying spontaneous liver allograft tolerance remains unclear. Given recent reports on the key role of recipient mouse dendritic cells (DCs) in host spleens expressing intact donor MHC (cross-dressing) in the instigation of graft rejection, we sought to investigate the role of cross-dressed DCs in liver transplantation tolerance.

Methods: Liver allografts from C57BL/6 (B6; H-2b) or B6 SJL CD45.1 mice to C3H/HeJ (C3H; H-2k) recipients were performed. In this combination, unlike heart, skin or kidney allografts, > 90% liver grafts are accepted without immunosuppressive therapy. Graft non-parenchymal cells (NPC) and splenocytes were examined by flow cytometry and imaging cytometry on post-operative days (POD) 1, 3, 7, 14, 30, and 300. Mixed leucocyte reactions (CFSE-MLR) were also performed to assess DC function.

Results: Infiltration by recipient DCs (lineage (-), CD11c (+)) in liver allografts peaked on POD 7, while donor DCs in liver grafts gradually disappeared and could not be detected by POD 7. Interestingly, more than half of the graft-infiltrating recipient DCs at that time displayed donor MHC-I, indicating cross-dressing; these DCs persisted in the graft (approx. 20 % of recipient DC) at least until POD 300. In contrast, only a very minor fraction of cross-dressed DCs (CD-DC) (0-2%) were detected in the spleen at any time point. Control staining for donor MHC-I using naïve C3H mouse liver NPC or splenocytes was negative. Moreover, especially on POD 7, and persisting until POD 300, CD-DC from liver grafts expressed higher levels of T cell inhibitory programed death ligand 1 (PD-L1) compared to non cross-dressed DC (nCD-DC). Importantly, unlike nCD-DC, CD-DC from liver grafts or spleens did not stimulate proliferation of allo-reactive B6 T cells in CFSE-MLR.

Conclusions: A large proportion of recipient CD-DC with inability to induce T cell alloreactivity is evident in liver allografts early post-transplant. Moreover, cross-dressing by graft-infiltrating DCs that also express high levels of PD-L1, persists indefinitely. This suggests that graft-infiltrating host CD-DC may play a key role in regulation of alloimmunity and the promotion of donor-specific liver transplant tolerance.

CITATION INFORMATION: Ono Y, Perez Gutierrez A, Yokota S, Yoshida O, Nakao T, Camirand G, Geller D, Thomson A. Prominence of Graft-Infiltrating PD-L1^hi Cross-Dressed Dendritic Cells in Mouse Liver Transplant Tolerance. Am J Transplant. 2017;17 (suppl 3).

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