Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Room EE1.17, 2333 CC Leiden, the Netherlands.
HMC Westeinde, The Hague, the Netherlands.
Cardiovasc Res. 2019 Mar 15;115(4):729-738. doi: 10.1093/cvr/cvy261.
T lymphocytes play an important role in atherosclerosis development, but the role of the CD8+ T-cell remains debated, especially in the clinically relevant advanced stages of atherosclerosis development. Here, we set out to determine the role of CD8+ T-cells in advanced atherosclerosis.
Human endarterectomy samples analysed by flow cytometry showed a negative correlation between the percentage of CD8+ T-cells and macrophages, suggesting a possible protective role for these cells in lesion development. To further test this hypothesis, LDLr-/- mice were fed a western-type diet (WTD) for 10 weeks to induce atherosclerosis, after which they received CD8α-depleting or isotype control antibody for 6 weeks. Depletion of CD8+ T-cells in advanced atherosclerosis resulted in less stable lesions, with significantly reduced collagen content in the trivalve area, increased macrophage content and increased necrotic core area compared with controls. Mechanistically, we observed that CD8 depletion specifically increased the fraction of Th1 CD4+ T-cells in the lesions. Treatment of WTD-fed LDLr-/- mice with a FasL-neutralizing antibody resulted in similar changes in macrophages and CD4+ T-cell skewing as CD8+ T-cell depletion.
These findings demonstrate for the first time a local, protective role for CD8+ T-cells in advanced atherosclerosis, through limiting accumulation of Th1 cells and macrophages, identifying a novel regulatory mechanism for these cells in atherosclerosis.
T 淋巴细胞在动脉粥样硬化发展中发挥重要作用，但 CD8+T 细胞的作用仍存在争议，尤其是在动脉粥样硬化发展的临床相关晚期阶段。在此，我们旨在确定 CD8+T 细胞在晚期动脉粥样硬化中的作用。
通过流式细胞术分析人类动脉内膜切除术样本显示，CD8+T 细胞与巨噬细胞的百分比呈负相关，表明这些细胞在病变发展中可能具有保护作用。为了进一步验证这一假说，我们用西方饮食（WTD）喂养 LDLr-/- 小鼠 10 周以诱导动脉粥样硬化，之后用 CD8α 耗竭或同型对照抗体治疗 6 周。与对照组相比，晚期动脉粥样硬化中 CD8+T 细胞的耗竭导致斑块更不稳定，三尖瓣区域的胶原含量显著降低，巨噬细胞含量增加，坏死核心面积增加。从机制上讲，我们观察到 CD8 耗竭特异性增加了病变中 Th1 CD4+T 细胞的分数。用 FasL 中和抗体治疗 WTD 喂养的 LDLr-/- 小鼠，与 CD8+T 细胞耗竭一样，导致巨噬细胞和 CD4+T 细胞偏倚发生类似变化。
这些发现首次证明了 CD8+T 细胞在晚期动脉粥样硬化中具有局部保护作用，通过限制 Th1 细胞和巨噬细胞的积累，为这些细胞在动脉粥样硬化中的调节机制提供了新的认识。
