Although 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. We investigated the role of intragraft dendritic cells (DCs) and cross‐dressing in mouse major histocompatibility complex (MHC)‐mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. Although donor interstitial DCs diminished rapidly after transplantation, they were replaced in the liver by host DCs that peaked on postoperative day (POD) 7 and persisted indefinitely. Approximately 60% of these recipient DCs displayed donor MHC class I, indicating cross‐dressing. By contrast, only a very minor fraction (0%‐2%) of cross‐dressed DCs (CD‐DCs) was evident in the spleen. CD‐DCs sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD‐L1) and high levels of interleukin‐10 compared with non–CD‐DCs (nCD‐DCs) 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. Unlike nCD‐DCs, the CD‐DCs failed to stimulate proliferation of allogeneic T cells but markedly suppressed antidonor host T cell proliferation. CD‐DCs were much less evident in allografts from DNAX‐activating protein of 12 kDa (DAP12)−/− donors that were rejected acutely. Conclusion: These findings suggest that graft‐infiltrating PD‐L1hi CD‐DCs may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. (Hepatology 2018;67:1499‐1515)

中文翻译：

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移植物浸润 PD-L1hi 异装树突状细胞调节小鼠肝移植耐受中的抗供体 T 细胞反应

尽管已经确定了换药在对病毒感染的免疫中以及最近在引起移植排斥中的关键作用，但其在耐受性中的作用尚不清楚。我们研究了移植内树突状细胞 (DC) 和交叉敷料在小鼠主要组织相容性复合体 (MHC) 不匹配的肝移植耐受中的作用，这种耐受性在没有治疗性免疫抑制的情况下发生。尽管供体间质 DC 在移植后迅速减少，但它们在肝脏中被宿主 DC 所取代，宿主 DC 在术后第 7 天达到峰值并无限期地持续存在。大约 60% 的这些受体 DC 显示供体 MHC I 类，表明易装。相比之下，脾脏中只有极少部分 (0%-2%) 的交叉穿衣 DC (CD-DC) 是明显的。与从移植物分离的非 CD-DCs (nCD-DCs) 相比，从肝移植物中分选出来的 CD-DCs 表达了更高水平的 T 细胞抑制性程序性死亡配体 1 (PD-L1) 和高水平的白细胞介素-10。同时，观察到程序性死亡蛋白 1 (PD-1)hi T 细胞免疫球蛋白和含有 3 (TIM-3)+ 耗尽的移植物浸润 CD8+ T 细胞的粘蛋白结构域的高发生率。与 nCD-DC 不同，CD-DC 不能刺激同种异体 T 细胞的增殖，但显着抑制了抗供体宿主 T 细胞的增殖。CD-DC 在来自 12 kDa (DAP12)-/- 供体的 DNAX 激活蛋白的同种异体移植物中明显不明显，这些供体被急性排斥。结论：这些发现表明，移植物浸润的 PD-L1hi CD-DC 可能在调节同种免疫和诱导肝移植耐受中起关键作用。