Expression of functional tissue factor in activated T-lymphocytes in vitro and in vivo: A possible contribution of immunity to thrombosis?
Expression of functional tissue factor in activated T-lymphocytes in vitro and in vivo: A possible contribution of immunity to thrombosis?
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DOI：
10.1016/j.ijcard.2016.04.177
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发表时间：
2016-09-01
影响因子：
3.5
通讯作者：
Cimmino, Giovanni
中科院分区：
文献类型：
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作者：
De Palma, Raffaele;Cirillo, Plinio;Cimmino, Giovanni
目的：T淋巴细胞激活在急性冠状动脉综合征（ACS）的病理生理学中发挥重要作用。 ACS 患者的斑块显示出 T 细胞的选择性寡克隆扩增，表明不稳定病变内存在特异性、抗原驱动的 T 淋巴细胞募集。然而，目前尚不清楚 T 细胞是否可以通过表达功能性组织因子 (TF) 直接导致血栓形成。因此，本研究的目的是调查 T 细胞在激活状态下是否能够表达功能性 TF。 方法：在体外，用抗 CD3/CD28 珠、IL-6、TNF-α、IL-17、INF-gamma 或 PMA/离子霉素刺激从血沉棕黄层分离的 CD3(+) 细胞。刺激后，测量了细胞表面基因和蛋白质水平上的 TF 表达，以及全细胞和微粒中的促凝血活性。在体内，对从 ACS-NSTEMI 和稳定型冠状动脉疾病 (SCAD) 患者的主动脉和冠状窦中分离的 CD3(+) 细胞中的 TF 表达进行了评估。还通过免疫组织化学评估了 ACS-STEMI 患者抽吸的血栓中 CD3(+)-TF+ 细胞的存在。结果：PMA/离子霉素和 IL-17 加 INF-gamma 刺激导致基因和蛋白质水平以及细胞表面表达的 TF 显着增加。这伴随着全细胞和微粒中 FXa 生成的平行增加，表明诱导的膜结合 TF 具有活性。此外，与 SCAD 患者相比，从 ACS 患者获得的 CD3(+) 细胞的经心 TF 梯度显着更高。有趣的是，ACS-STEMI 患者的血栓富含 CD3(+) 细胞，其中大多数表达 TF。结论：我们的数据表明，体外活化的 T 淋巴细胞在其膜上表达功能性 TF，表明这些细胞在血栓形成过程中具有直接的病理生理学作用；体内观察结果进一步支持了这一假设，即来自 ACS-NSTEMI 患者冠状动脉循环的 CD3(+) 细胞显示出 TF 水平升高，并且来自 ACS-STEMI 患者的冠状动脉血栓富含表达 TF 的 CD3(+) 细胞。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
Objective: T-lymphocyte activation plays an important role in the pathophysiology of acute coronary syndromes (ACS). Plaques from ACS patients show a selective oligoclonal expansion of T-cells, indicating a specific, antigen-driven recruitment of T-lymphocytes within the unstable lesions. At present, however, it is not known whether T-cells may contribute directly to thrombosis by expressing functional tissue factor (TF). Accordingly, the aim of the present study was to investigate whether T-cells are able to express functional TF in their activated status.Methods: In vitro, CD3(+)-cells, isolated from buffy coats, were stimulated with anti-CD3/CD28 beads, IL-6, TNF-alpha, IL-17, INF-gamma or PMA/ionomycin. Following stimulation, TF expression on cell-surface, at gene and protein levels, as well as its procoagulant activity in whole cells and microparticles was measured. In vivo, TF expression was evaluated in CD3(+)-cells isolated from the aorta and the coronary sinus of ACS-NSTEMI and stable coronary artery disease (SCAD) patients. The presence of CD3(+)-TF+ cells was also evaluated by immunohistochemistry in thrombi aspirated from ACS-STEMI patients.Results: PMA/ionomycin and IL-17 plus INF-gamma stimulation resulted in a significant TF increase at gene and protein levels as well as at cell-surface expression. This was accompanied by a parallel increase in FXa generation, both in whole cells and in microparticles, indicating that the induced membrane-bound TF was active. Furthermore, transcardiac TF gradient was significantly higher in CD3(+)-cells obtained from ACS-patients compared to SCAD-patients. Interestingly, thrombi from ACS-STEMI patients resulted enriched in CD3(+)-cells, most of them expressing TF.Conclusions: Our data demonstrate that activated T-lymphocytes in vitro express functional TF on their membranes, suggesting a direct pathophysiological role of these cells in the thrombotic process; this hypothesis is further supported by the observations in vivo that CD3(+)-cells from coronary circulation of ACS-NSTEMI patients show increased TF levels and that coronary thrombi from ACS-STEMI patients are enriched in CD3(+)-cells expressing TF. (C) 2016 Elsevier Ireland Ltd. All rights reserved.