Li Jie, McArdle Sara, Gholami Amin, Kimura Takayuki, Wolf Dennis, Gerhardt Teresa, Miller Jacqueline, Weber Christian, Ley Klaus
From the Division of Inflammation Biology (J.L., S.M., T.K., D.W., T.G., J.M., K.L.) and Bioinformatics Core (A.G.), La Jolla Institute for Allergy & Immunology, CA; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.W.).
Circ Res. 2016 May 13;118(10):1540-52. doi: 10.1161/CIRCRESAHA.116.308648. Epub 2016 Mar 28.
CD4 T cells are involved in the pathogenesis of atherosclerosis, but atherosclerosis-specific CD4 T cells have not been described. Moreover, the chemokine(s) that regulates T-cell trafficking to the atherosclerotic lesions is also unknown.
In Apoe(-/-) mice with mature atherosclerotic lesions (5 months of high fat diet), we find that most aortic T cells express CCR5 and interferon-γ with a unique combination of cell surface markers (CD4(+)CD25(-)CD44(hi)CD62L(lo)) and transcription factors (FoxP3(+)T-bet(+)). We call these cells CCR5Teff. We investigated the role of CCR5 in regulating T-cell homing to the atherosclerotic aorta and the functionality of the CCR5Teff cells.
CCR5Teff cells are exclusively found in the aorta and para-aortic lymph nodes of Apoe(-/-) mice. They do not suppress T-cell proliferation in vitro and are less potent than regulatory T cells at inhibiting cytokine secretion. Blocking or knocking out CCR5 or its ligand CCL5 significantly blocks T-cell homing to atherosclerotic aortas. Transcriptomic analysis shows that CCR5Teff cells are more similar to effector T cells than to regulatory T cells. They secrete interferon-γ, interleukin-2, interleukin-10, and tumor necrosis factor. Adoptive transfer of these CCR5Teff cells significantly increases atherosclerosis.
CCR5 is specifically needed for CD4 T-cell homing to the atherosclerotic plaques. CCR5(+)CD4 T cells express an unusual combination of transcription factors, FoxP3 and T-bet. Although CCR5Teff express FoxP3, we showed that they are not regulatory and adoptive transfer of these cells exacerbates atherosclerosis.
CD4 T细胞参与动脉粥样硬化的发病机制，但尚未描述过动脉粥样硬化特异性CD4 T细胞。此外，调节T细胞向动脉粥样硬化病变部位迁移的趋化因子也尚不清楚。
在具有成熟动脉粥样硬化病变（高脂饮食5个月）的Apoe(-/-)小鼠中，我们发现大多数主动脉T细胞表达CCR5和干扰素-γ，具有独特的细胞表面标志物（CD4(+)CD25(-)CD44(hi)CD62L(lo)）和转录因子组合（FoxP3(+)T-bet(+)）。我们将这些细胞称为CCR5Teff。我们研究了CCR5在调节T细胞归巢至动脉粥样硬化主动脉中的作用以及CCR5Teff细胞的功能。
CCR5Teff细胞仅在Apoe(-/-)小鼠的主动脉和主动脉旁淋巴结中发现。它们在体外不抑制T细胞增殖，并且在抑制细胞因子分泌方面比调节性T细胞效力更低。阻断或敲除CCR5或其配体CCL5可显著阻断T细胞归巢至动脉粥样硬化主动脉。转录组分析表明，CCR5Teff细胞与效应T细胞比与调节性T细胞更相似。它们分泌干扰素-γ、白细胞介素-2、白细胞介素-10和肿瘤坏死因子。这些CCR5Teff细胞的过继转移显著增加动脉粥样硬化。
CD4 T细胞归巢至动脉粥样硬化斑块特别需要CCR5。CCR5(+)CD4 T细胞表达转录因子FoxP3和T-bet的异常组合。尽管CCR5Teff表达FoxP3，但我们表明它们不是调节性的，并且这些细胞的过继转移会加剧动脉粥样硬化。
