CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets
CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets
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DOI：
10.1002/hep.21017
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发表时间：
2006-02-01
期刊：
影响因子：
13.5
通讯作者：
Krombach, F
中科院分区：
文献类型：
--
作者：
Khandoga, A;Hanschen, M;Krombach, F
在抗原非依赖性缺血/再灌注（I/R）期间，T细胞参与肝脏炎症的机制尚未完全了解。我们分析了体内缺血后肝脏微循环中T细胞的募集，并测试了T细胞与血小板相互作用并激活窦状隙内皮细胞，导致微血管功能障碍，随后组织损伤的假设。使用活体视频荧光显微镜，我们在小鼠中发现，在早期再灌注期间，热肝I/R（90/30-140 min）诱导CD 4（+）T细胞在血窦中的积聚和跨内皮迁移，但不诱导CD 8（+）T细胞在血窦中的积聚和跨内皮迁移。荧光标记的CD 4（+）T细胞和血小板的同时可视化显示，大约30%的所有累积的CD 4（+）T细胞与血小板共定位，表明两种细胞类型之间的相互作用。尽管野生型小鼠中CD 4（+）/CD 40 L（-/-）T细胞与CD 40 L（-/-）血小板的相互作用略有减少，但如果CD 4（+）T细胞和血小板来自CD 62 P（-/-）小鼠，则它们几乎不存在。CD 4缺乏以及CD 40-CD 40 L和CD 28-B7破坏以与糖蛋白IIb/IIIa拮抗剂的血小板失活相同的方式减弱缺血后血小板粘附，并减少中性粒细胞迁移、窦灌注衰竭和转氨酶活性。然而，用MHC II类抗体治疗并不影响I/R损伤。总之，我们描述的类型，动力学和微血管定位的T细胞募集在缺血后的肝脏。CD 4（+）T细胞在缺血后血窦中与血小板相互作用，这种相互作用由血小板CD 62 P介导。CD 4（+）T细胞激活内皮细胞，通过CD 40-CD 40 L和CD 28-B7依赖性途径增加I/R诱导的血小板粘附和中性粒细胞迁移，并加重微血管/肝细胞损伤。
The mechanisms by which T cells contribute to the hepatic inflammation during antigen-independent ischemia/reperfusion (I/R) are not fully understood. We analyzed the recruitment of T cells in the postischemic hepatic microcirculation in vivo and tested the hypothesis that T cells interact with platelets and activate sinusoidal endothelial cells, resulting in microvascular dysfunction followed by tissue injury. Using intravital videofluorescence microscopy, we show in mice that warm hepatic I/R (90/30-140 min) induces accumulation and transendothelial migration of CD4(+), but not CD8(+) T cells in sinusoids during early reperfusion. Simultaneous visualization of fluorescence-labeled CD4(+) T cells and platelets showed that approximately 30% of all accumulated CD4(+) T cells were colocalized with platelets, suggesting an interaction between both cell types. Although interactions of CD4(+)/CD40L(-/-) T cells with CD40L(-/-) platelets in wild-type mice were slightly reduced, they were almost absent if CD4(+) T cells and platelets were from CD62P(-/-) mice. CD4 deficiency as well as CD40-CD40L and CD28-B7 disruption attenuated postischemic platelet adherence in the same manner as platelet inactivation with a glycoprotein IIb/IIIa antagonist and reduced neutrophil transmigration, sinusoidal perfusion failure, and transaminase activities. Treatment with an MHC class II antibody, however, did not affect I/R injury. In conclusion, we describe the type, kinetic, and microvascular localization of T cell recruitment in the postischemic liver. CD4(+) T cells interact with platelets in postischemic sinusoids, and this interaction is mediated by platelet CD62P. CD4(+) T cells activate endothelium, increase I/R-induced platelet adherence and neutrophil migration via CD40-CD40L and CD28-B7-dependent pathways, and aggravate microvascular/hepatocellular injury.