Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury.
Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury.
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DOI：
10.1016/j.jhep.2014.10.034
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发表时间：
2015-03
影响因子：
25.7
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Liu, Yuanxing;Ji, Haofeng;Zhang, Yu;Shen, Xiuda;Gao, Feng;He, Xiangyi;Li, Gabriella A.;Busuttil, Ronald W.;Kuchroo, Vijay K.;Kupiec-Weglinski, Jerzy W.
通过与活化的Th 1细胞上的T细胞免疫球蛋白粘蛋白-3（TIM-3）结合，半乳糖凝集素-9（Gal-9）负调节Th 1型同种异体免疫。虽然T细胞参与肝脏缺血再灌注损伤（IRI），但尚不清楚负性T细胞依赖性TIM-3共刺激是否可以拯救IR应激的原位肝移植（奥尔特）免于先天免疫驱动的炎症。我们使用WT和TIM-3 Tg小鼠（C57 BL 6）作为肝脏冷藏（在UW溶液中4°C下20小时）和同基因奥尔特的临床相关模型中的肝脏供体和受体。WT或TIM-3 Tg->TIM-3 Tg组中的OLT对IR应激具有抗性，这由保留的肝细胞功能（sALT水平）和肝脏结构（Suzuki评分）证明。相反，WT或TIM-3 Tg->WT组中的OLT对IRI敏感。受体循环CD 4 + T细胞中的TIM-3诱导：1/抑制Tbet/IFN-γ，同时扩增OLT中的GATA 3和IL-4/IL-10表达; 2/促进T细胞耗竭（PD-1、LAG-3）表型; 3/抑制OLT中的中性粒细胞和巨噬细胞浸润/功能。在平行研究中，我们首次记录了Gal-9（一种天然TIM-3配体）主要由IR应激肝细胞在体内和体外产生和释放。此外，外源性rGal-9通过抑制T细胞活化和促进CD 4 + T细胞凋亡来增强肝脏对IRI的抵抗。利用T细胞-肝细胞界面处的TIM-3-Gal-9信号传导促进IR应激的OLT中的稳态。增强抗氧化肝细胞Gal-9增强肝脏IR抗性。受体TIM-3+ CD 4+细胞的负调节为离散T细胞亚群的细胞保护功能提供了证据，当在移植受体中应用T细胞靶向免疫抑制时，这些T细胞亚群应该被保留。
By binding to T-cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, Galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 costimulation may rescue IR-stressed orthotopic liver transplants (OLT) from innate immunity-driven inflammation. We used WT and TIM-3Tg mice (C57BL6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20h at 4°C in UW solution) and syngeneic OLT. OLTs in WT or TIM-3Tg->TIM-3Tg groups were resistant against IR- stress, evidenced by preserved hepatocellular function (sALT levels) and liver architecture (Suzuki’s score). In contrast, OLTs in WT or TIM-3Tg->WT groups were susceptible to IRI. TIM-3 induction in recipient circulating CD4+ T cells: 1/ depressed Tbet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in OLTs; 2/ promoted T cell exhaustion (PD-1, LAG-3) phenotype; and 3/ depressed neutrophil and macrophage infiltration/function in OLTs. In parallel studies, we have documented, for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in-vivo and in-vitro. Moreover, exogenous rGal-9 potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells. Harnessing TIM-3–Gal-9 signaling at T cell–hepatocyte interface facilitates homeostasis in IR-stressed OLTs. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.
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影响因子：
4.3
作者：
Hansen, John A.;Hanash, Samir M.;Tabellini, Laura;Baik, Chris;Lawler, Richard L.;Grogan, Bryan M.;Storer, Barry;Chin, Alice;Johnson, Melissa;Wong, Chee-Hong;Zhang, Qing;Martin, Paul J.;McDonald, George B.
通讯作者：
McDonald, George B.
影响因子：
3
作者：
Hirashima, M;Kashio, Y;Nakamura, T
通讯作者：
Nakamura, T
影响因子：
3.7
作者：
Moritoki M;Kadowaki T;Niki T;Nakano D;Soma G;Mori H;Kobara H;Masaki T;Kohno M;Hirashima M
通讯作者：
Hirashima M
影响因子：
64.8
作者：
Monney, L;Sabatos, CA;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
13.5
作者：
Pommey, Sandra;Lu, Bo;Dwyer, Karen M.
通讯作者：
Dwyer, Karen M.