Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts
Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts
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DOI：
10.1172/jci125773
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发表时间：
2020-01-01
影响因子：
15.9
通讯作者：
Lakkis, Fadi G.
中科院分区：
文献类型：
--
作者：
Hughes, Andrew D.;Zhao, Daqiang;Lakkis, Fadi G.
介导同种异体移植物排斥的宿主T细胞的活化是一个2步过程。第一种发生在次级淋巴器官中，其中T细胞遇到宿主DC呈递的同种抗原并分化为效应物。在这些位点的抗原呈递主要通过将完整的供体MHC-肽复合物从移植细胞转移到宿主DC（cross-dressing）或通过将供体抗原摄取和加工成与自身MHC分子结合的同种肽（间接呈递）而发生。第二步发生在移植物中，其中效应T细胞在引起排斥反应之前与宿主DC重新接合。宿主DC如何将同种抗原呈递给移植物中的T细胞尚不清楚。使用小鼠胰岛和肾移植模型，成像细胞术，和2-光子活体显微镜，我们证明了广泛的cross-dressing移植物内宿主DC与供体MHC-肽复合物发生移植后早期，而通过间接途径呈递供体抗原的宿主DC是罕见的。交叉修饰的DC稳定地与TCR转基因效应CD 8（+）T细胞结合，这些细胞识别供体抗原，足以维持急性排斥反应。在慢性肾排斥模型中，异装随着时间的推移而下降，但在移植后8周仍很明显。我们的结论是宿主DC与供体MHC分子的交叉装扮是同种异体移植物内驱动效应T细胞应答的主要抗原呈递途径。
Activation of host T cells that mediate allograft rejection is a 2-step process. The first occurs in secondary lymphoid organs where T cells encounter alloantigens presented by host DCs and differentiate to effectors. Antigen presentation at these sites occurs principally via transfer of intact, donor MHC-peptide complexes from graft cells to host DCs (cross-dressing) or by uptake and processing of donor antigens into allopeptides bound to self-MHC molecules (indirect presentation). The second step takes place in the graft, where effector T cells reengage with host DCs before causing rejection. How host DCs present alloantigens to T cells in the graft is not known. Using mouse islet and kidney transplantation models, imaging cytometry, and 2-photon intravital microscopy, we demonstrate extensive cross-dressing of intragraft host DCs with donor MHC-peptide complexes that occurred early after transplantation, whereas host DCs presenting donor antigen via the indirect pathway were rare. Cross-dressed DCs stably engaged TCR-transgenic effector CD8(+) T cells that recognized donor antigen and were sufficient for sustaining acute rejection. In the chronic kidney rejection model, cross-dressing declined over time but was still conspicuous 8 weeks after transplantation. We conclude that cross-dressing of host DCs with donor MHC molecules is a major antigen presentation pathway driving effector T cell responses within allografts.