Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution
Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution
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DOI：
10.1161/circresaha.116.309301
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发表时间：
2016-12-09
影响因子：
20.1
通讯作者：
Becker, Christian
中科院分区：
文献类型：
--
作者：
Luther, Natascha;Shahneh, Fatemeh;Becker, Christian
理由：免疫细胞在血栓形成和消退过程中起重要作用。T细胞是免疫和非免疫细胞功能的强大调节剂，然而，它们在无菌炎症和静脉血栓形成中的作用尚未得到系统的研究。目的：研究T细胞在深静脉血栓形成中的募集、活化和炎症活性及其对静脉血栓溶解的影响。方法与结果：CD4（+）和CD8(+) T细胞在深静脉血栓形成诱导过程中迅速浸润血栓和静脉壁，并在血栓溶解过程中一直留在组织中。在静脉壁上，募集的T细胞主要由效应记忆T （T- em）细胞组成。使用t细胞受体转基因报告小鼠，我们证明深静脉血栓募集的T-EM立即接受抗原非依赖性激活，并原位产生ifn - γ（干扰素）。绘制血栓形成静脉的炎症状况，我们确定了一组深静脉血栓形成上调的细胞因子和趋化因子，它们协同诱导CD4（+）和CD8(+) T-EM细胞中抗原不依赖的ifn - γ产生。通过耗竭恢复过程减少T-EM细胞的数量，我们发现静脉T-EM激活决定中性粒细胞和单核细胞的募集，并延迟血栓的新生血管和溶解。检查T细胞募集在人类静脉停滞，我们发现浅表静脉曲张优先包含活化记忆T细胞。结论：T-EM调节静脉血栓形成的炎症反应，影响血栓的溶解。
Rationale: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined.Objective: This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution.Methods and Results: CD4(+) and CD8(+) T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (T-EM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited T-EM receive an immediate antigen-independent activation and produce IFN-gamma (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-gamma production in CD4(+) and CD8(+) T-EM cells. Reducing the number of T-EM cells through a depletion recovery procedure, we show that intravenous T-EM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells.Conclusions: T-EM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.