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Cross-dressed dendritic cells sustain effector T cell responses in islet and kidney allografts
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2019-11-25 , DOI: 10.1172/jci125773
Andrew D. Hughes , Daqiang Zhao , Hehua Dai , Khodor I. Abou-Daya , Roger Tieu , Rayan Rammal , Amanda L. Williams , Douglas P. Landsittel , Warren D. Shlomchik , Adrian E. Morelli , Martin H. Oberbarnscheidt , Fadi G. Lakkis

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.

中文翻译:

混杂的树突状细胞在胰岛和肾脏同种异体移植物中维持效应T细胞反应

介导同种异体排斥反应的宿主T细胞的激活是一个两步过程。第一次发生在继发性淋巴器官中,其中T细胞遇到宿主DC呈现的同种抗原并分化为效应子。这些位点上的抗原提呈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上(交叉换装)或通过将供体抗原摄取和加工成与自身MHC分子结合的全肽(间接提呈)而发生。第二步发生在移植物中,其中效应T细胞在引起排斥之前与宿主DC重新结合。宿主DC如何向移植物中的T细胞呈现同种抗原。使用小鼠胰岛和肾脏移植模型,成像细胞计数和2光子活体显微镜检查,我们证明了移植后宿主DC与供体MHC-肽复合物的广泛异装现象在移植后早期发生,而通过间接途径呈递供体抗原的宿主DC很少。横穿DC稳定地参与TCR转基因效应物CD8+ T细胞能够识别供体抗原,足以维持急性排斥反应。在慢性肾脏排斥模型中,换药随时间推移而下降,但在移植后8周仍显着。我们得出结论,宿主DC与供体MHC分子的伪装是驱动同种异体移植物中效应T细胞反应的主要抗原呈递途径。
更新日期:2020-01-04
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