CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.
CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.
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DOI：
10.1371/journal.ppat.1008885
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发表时间：
2020-09
期刊：
影响因子：
6.7
通讯作者：
Freeman ML
中科院分区：
文献类型：
--
作者：
Panigrahi S;Chen B;Fang M;Potashnikova D;Komissarov AA;Lebedeva A;Michaelson GM;Wyrick JM;Morris SR;Sieg SF;Paiardini M;Villinger FJ;Harth K;Kashyap VS;Cameron MJ;Cameron CM;Vasilieva E;Margolis L;Younes SA;Funderburg NT;Zidar DA;Lederman MM;Freeman ML
动脉粥样硬化性心血管疾病（ASCVD）仍然是普通人群发病的重要原因，艾滋病毒感染者（PLWH）患ASCVD的风险增加了约2倍。这种风险与动脉粥样硬化斑块中丰富的CD8 T细胞计数升高有关，CD8 T细胞计数与疾病发病机制有关，但驱动T细胞募集和激活斑块的机制尚不明确。在这里，我们研究了CD8 T细胞在非人类HIV感染灵长类动物模型和未感染HIV的老年人动脉粥样硬化中的作用；我们试图确定促进CX3CR1+ CD8 T细胞的激活、功能和内皮募集的因素。我们测量了感染SIV或SHIV的恒河猴主动脉中CX3CL1和IL-15的表达升高，CD8 T细胞数量增加，并在未感染hiv的人的动脉粥样硬化血管中证实了类似的结果。我们发现重组TNF增强了主动脉内皮细胞中CX3CL1和生物活性IL-15的产生和释放，而主动脉平滑肌细胞中则没有。IL-15反过来促进CX3CR1在CD8 T细胞表面的表达和TNF的合成，并且IL-15处理的CD8 T细胞对内皮细胞表现出增强的cx3cl1依赖性的化学吸引力。最后，我们发现人类动脉粥样硬化斑块中的CD8 T细胞具有激活的常驻表型，与体内IL-15和CX3CL1暴露一致。在本报告中，我们定义了一种CD8 T细胞参与动脉粥样硬化的新模型，其中CX3CL1和IL-15在血管内皮内协同作用，促进活化的CX3CR1+记忆性CD8 T细胞的浸润，通过TNF进一步驱动内皮细胞活化。我们认为这些相互作用在衰老和PLWH中普遍存在，在这些人群中，循环激活的CX3CR1+ CD8 T细胞数量经常增加。HIV感染者和未感染HIV的老年人发生动脉粥样硬化性心血管疾病的风险增加，并且表达血管内皮归巢受体CX3CR1的CD8 T细胞数量和/或比例增加。动脉粥样硬化斑块含有许多活化的CD8 T细胞，这些细胞与疾病的发病机制有关，但驱动T细胞募集和活化斑块的机制尚不清楚。在这里，我们提出了一个模型，其中CX3CR1+ CD8 T细胞通过CX3CL1、IL-15和TNF的联合作用促进内皮功能障碍。持续的炎症会引发HIV感染者内皮细胞的激活和功能障碍。内皮细胞衍生的CX3CL1然后引导CX3CR1+ T细胞迁移到活化的内皮，在那里IL-15激活T细胞表达TNF。TNF驱动内皮细胞表达CX3CL1和IL-15，提供一个前馈激活循环。我们提供的证据表明，这些途径在人类动脉粥样硬化斑块和SIV/ shiv感染的恒河猴的主动脉内皮中是活跃的。我们认为这些T细胞诱导的内皮损伤机制在普通人群中传统危险因素相关的动脉粥样硬化中是有效的，并且在持续慢性炎症状态的HIV感染者中加速。
Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded. People living with HIV infection and elderly HIV-uninfected persons have increased risk of developing atherosclerotic cardiovascular disease, and have increased numbers and/or proportions of CD8 T cells that express the vascular endothelium-homing receptor CX3CR1. Atherosclerotic plaques contain many activated CD8 T cells, which have been implicated in disease pathogenesis, yet the mechanisms driving T cell recruitment to and activation within plaques are not clear. Here we propose a model in which CX3CR1+ CD8 T cells promote endothelial dysfunction by the combined effects of CX3CL1, IL-15, and TNF. Persistent inflammation triggers endothelial cell activation and dysfunction in people living with HIV infection. Endothelial cell-derived CX3CL1 then directs the migration of CX3CR1+ T cells to the activated endothelium where IL-15 activates T cells to express TNF. TNF drives endothelial expression of CX3CL1 and IL-15, providing a feed-forward loop of activation. We provide evidence that these pathways are active in human atherosclerotic plaques and in the aortic endothelium of SIV/SHIV-infected rhesus macaques. We propose these mechanisms of T cell-induced endothelial damage are operative in traditional risk factor-associated atherosclerosis in the general population and are accelerated in people with HIV infection who live in a state of sustained chronic inflammation.
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影响因子：
3.8
作者：
Castillo, Eliseo F.;Schluns, Kimberly S.
通讯作者：
Schluns, Kimberly S.
影响因子：
3.8
作者：
Nastasie MS;Thissen H;Jans DA;Wagstaff KM
通讯作者：
Wagstaff KM
影响因子：
5
作者：
Kyaw, Tin;Tipping, Peter;Bobik, Alex
通讯作者：
Bobik, Alex
DOI：
10.1161/01.atv.0000190672.36490.7b
发表时间：
2005-12-01
影响因子：
8.7
作者：
Damås, JK;Boullier, A;Quehenberger, O
通讯作者：
Quehenberger, O
DOI：
10.1073/pnas.092675799
发表时间：
2002-04-30
影响因子：
11.1
作者：
Liu, KB;Catalfamo, M;Weng, NP
通讯作者：
Weng, NP