Graft-infiltrating PD-L1hi cross-dressed dendritic cells regulate anti-donor T cell responses in mouse liver transplant tolerance

Abstract

While a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. Here, we investigated the role of intra-graft dendritic cells (DC) and cross-dressing in mouse major histocompatibility complex (MHC)-mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. While donor interstitial DC diminished rapidly following transplantation, they were replaced in the liver by host DC that peaked on postoperative day (POD) 7 and persisted indefinitely. About 60% of these recipient DC displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0-2%) of cross-dressed DC (CD-DC) was evident in the spleen. CD-DC sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of IL-10 compared with non CD-DC (nCD-DC) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)^hi T cell immunoglobulin and mucin domain containing-3 (TIM-3)⁺ exhausted graft-infiltrating CD8⁺ T cells were observed. Importantly, unlike nCD-DC, the CD-DC failed to stimulate proliferation of allogeneic T cells but markedly suppressed anti-donor host T cell proliferation. CD-DC were much less evident in allografts from DNAX-activating protein of 12kDa (DAP12)^-/- donors that were rejected acutely. Conclusion: These findings suggest that graft-infiltrating PD-L1^hi CD-DC may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. This article is protected by copyright. All rights reserved.

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