受体T细胞TIM-3和肝细胞半乳糖凝集素-9信号通路可保护小鼠肝移植免受缺血再灌注损伤。
Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury.
作者信息
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
机构信息
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA.
出版信息
J Hepatol. 2015 Mar;62(3):563-72. doi: 10.1016/j.jhep.2014.10.034. Epub 2014 Oct 31.
BACKGROUND & AIMS: 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 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation.
METHODS
We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT).
RESULTS
Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we 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 recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.
CONCLUSIONS
Harnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. 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.
背景与目的
通过与活化的Th1细胞上的T细胞免疫球蛋白黏蛋白-3（TIM-3）结合，半乳糖凝集素-9（Gal-9）对Th1型同种免疫起负向调节作用。尽管T细胞参与肝缺血再灌注损伤（IRI），但尚不清楚T细胞依赖性TIM-3共刺激的负向调节是否可使原位肝移植免受先天免疫驱动的炎症，从而挽救受缺血再灌注应激的原位肝移植。
方法
在一个临床相关的肝冷保存（在4℃UW溶液中保存20小时）和同基因原位肝移植（OLT）模型中，我们使用野生型（WT）和TIM-3转基因（Tg）小鼠（C57BL/6）作为肝供体和受体。
结果
WT或TIM-3Tg→TIM-3Tg组的原位肝移植对缺血再灌注应激具有抗性，这通过保留的肝细胞功能（血清ALT水平）和肝结构（铃木评分）得以证明。相比之下，WT或TIM-3Tg→WT组的原位肝移植对IRI敏感。受体循环CD4⁺T细胞中TIM-3的诱导：（1）抑制T-bet/IFN-γ，同时增强原位肝移植中GATA3和IL-4/IL-10的表达；（2）促进T细胞耗竭（PD-1、LAG-3）表型；（3）抑制原位肝移植中中性粒细胞和巨噬细胞的浸润/功能。在平行研究中，我们首次证明，天然TIM-3配体Gal-9在体内和体外主要由受缺血再灌注应激的肝细胞产生并释放。此外，外源性重组Gal-9（rGal-9）通过抑制T细胞活化和促进CD4⁺T细胞凋亡增强肝脏对IRI的抗性。
结论
利用T细胞-肝细胞界面的TIM-3/Gal-9信号传导有助于受缺血再灌注应激的原位肝移植维持内环境稳定。增强抗氧化的肝细胞Gal-9可增强肝脏对缺血再灌注的抗性。受体TIM-3⁺CD4⁺细胞的负向调节为离散T细胞亚群的细胞保护功能提供了证据，在对移植受者应用靶向T细胞的免疫抑制时应保留该亚群。
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