Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Am J Transplant. 2019 Mar;19(3):646-661. doi: 10.1111/ajt.15083. Epub 2018 Sep 17.
Mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 regulate the differentiation and function of immune cells. While inhibition of mTORC1 antagonizes dendritic cell (DC) differentiation and suppresses graft rejection, the role of mTORC2 in DCs in determining host responses to transplanted tissue remains undefined. Using a mouse model in which mTORC2 was deleted specifically in CD11c DCs (TORC2 ), we show that the transplant of minor histocompatibility Ag (HY)-mismatched skin grafts from TORC2 donors into wild-type recipients results in accelerated rejection characterized by enhanced CD8 T cell responses in the graft and regional lymphoid tissue [Correction added on January 9, 2019, after first online publication: in the previous sentence, major was changed to minor]. Similar enhancement of CD8 effector T cell responses was observed in MHC-mismatched recipients of TORC2 grafts. Augmented CD8 T cell responses were also observed in a delayed-type hypersensitivity model in which mTORC2 was absent in cutaneous DCs. These elevated responses could be ascribed to an increased T cell stimulatory phenotype of TORC2 and not to enhanced lymph node homing of the cells. In contrast, rejection of ovalbumin transgenic skin grafts in TORC2 recipients was unaffected. These findings suggest that mTORC2 in skin DCs restrains effector CD8 T cell responses and have implications for understanding of the influence of mTOR inhibitors that target mTORC2 in transplant.
雷帕霉素靶蛋白（mTOR）复合物（mTORC）1 和 mTORC2 调节免疫细胞的分化和功能。虽然抑制 mTORC1 拮抗树突状细胞（DC）分化并抑制移植物排斥，但 mTORC2 在决定宿主对移植组织反应中的作用在 DC 中仍未定义。我们使用一种模型，其中特异性在 CD11c DC（TORC2）中缺失 mTORC2，结果显示，从 TORC2 供体移植次要组织相容性 Ag（HY）错配皮肤移植物到野生型受体中会导致加速排斥，其特征是移植物和区域淋巴组织中增强的 CD8 T 细胞反应[2019 年 1 月 9 日在线发表后的更正：在前一句中，主要改为次要]。在 MHC 错配的 TORC2 移植物受体中也观察到 CD8 效应 T 细胞反应的类似增强。在皮肤 DC 中缺乏 mTORC2 的迟发型超敏反应模型中也观察到增强的 CD8 T 细胞反应。这些升高的反应可以归因于 TORC2 的 T 细胞刺激表型增加，而不是细胞对淋巴结归巢的增强。相比之下，在 TORC2 受体中，卵清蛋白转基因皮肤移植物的排斥不受影响。这些发现表明，皮肤 DC 中的 mTORC2 抑制效应 CD8 T 细胞反应，并对理解针对 mTORC2 的 mTOR 抑制剂在移植中的影响具有重要意义。
