The Requirement of CD8+ T Cells To Initiate and Augment Acute Cardiac Inflammatory Response to High Blood Pressure
The Requirement of CD8+ T Cells To Initiate and Augment Acute Cardiac Inflammatory Response to High Blood Pressure
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DOI：
10.4049/jimmunol.1301522
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发表时间：
2014-04-01
影响因子：
4.4
通讯作者：
Tang, Hong
中科院分区：
文献类型：
--
作者：
Ma, Feifei;Feng, Jin;Tang, Hong
心肌巨噬细胞浸润和活化是高血压引起急性心肌炎症反应的标志。然而，根本的机制仍然难以捉摸。在这篇文章中，我们报告了CD 8（+）T细胞是心脏募集和激活巨噬细胞所必需的。首先，用抗体去除CD 8基因靶向（CD 8敲除）或CD 8（+）T细胞的小鼠在血管紧张素II（Ang II）输注后对血压升高的心脏炎症反应显着降低，而用CD 8（+）T细胞重建的CD 8敲除小鼠恢复了对Ang II的敏感性。更重要的是，CD 8（+）T细胞是心肌中巨噬细胞浸润和随后活化以表达促炎细胞因子和趋化因子所必需的。此外，巨噬细胞活化需要与活化的CD 8（+）T细胞直接接触，但与TCR γ直接接触。在MHC I类限制性OVA特异性TCR转基因小鼠中进一步证实了巨噬细胞的TCR非依赖性活化，其显示出与野生型小鼠相似的CD 8（+）T细胞活化和对Ang II的心脏促炎反应。最后，只有心肌浸润的而不是外周的CD 8（+）T细胞被Ang II特异性激活，可能是通过驱动IFN-γ R+ CD 8（+）T细胞浸润和激活的心脏IFN-γ。因此，这项工作确定了CD 8（+）T细胞的非TCR依赖性先天性质，这对于启动对血压急性升高的无菌免疫反应至关重要。
Macrophage infiltration and activation in myocardium are hallmarks of acute cardiac inflammatory response to high blood pressure. However, the underlying mechanisms remain elusive. In this article, we report that CD8(+) T cells are required for cardiac recruitment and activation of macrophages. First, mice with CD8 gene-targeted (CD8 knockout) or CD8(+) T cells depleted by Ab showed significantly reduced cardiac inflammatory response to the elevation of blood pressure after angiotensin II (Ang II) infusion, whereas CD8 knockout mice reconstituted with CD8(+) T cells restored the sensitivity to Ang II. More importantly, CD8(+) T cells were required for macrophage infiltration in myocardium and subsequent activation to express proinflammatory cytokines and chemokines. Furthermore, macrophage activation required direct contact with activated CD8(+) T cells, but with TCR dispensable. TCR-independent activation of macrophages was further confirmed in MHC class I-restricted OVA-specific TCR transgenic mice, which showed a CD8(+) T cell activation and cardiac proinflammatory response to Ang II similar to that of wild-type mice. Finally, only myocardium-infiltrated, but not peripheral, CD8(+) T cells were specifically activated by Ang II, possibly by the cardiac IFN-gamma that drove IFN-gamma R+ CD8(+) T cell infiltration and activation. Thus, this work identified a TCR-independent innate nature of CD8(+) T cells that was critical in initiating the sterile immune response to acute elevation of blood pressure.