Cigarette Smoke Disturbs the Survival of CD8+ Tc/Tregs Partially through Muscarinic Receptors-Dependent Mechanisms in Chronic Obstructive Pulmonary Disease.
Cigarette Smoke Disturbs the Survival of CD8+ Tc/Tregs Partially through Muscarinic Receptors-Dependent Mechanisms in Chronic Obstructive Pulmonary Disease.
复制标题
香烟烟雾部分通过慢性阻塞性肺疾病中毒蕈碱受体依赖性机制扰乱 CD8 Tc/Treg 的存活。
DOI：
10.1371/journal.pone.0147232
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zhang JC
中科院分区：
文献类型：
--
作者：
Chen G;Zhou M;Chen L;Meng ZJ;Xiong XZ;Liu HJ;Xin JB;Zhang JC
已知CD 8 + T细胞（细胞毒性T细胞，Tc）在吸烟相关的气道炎症（包括慢性阻塞性肺病（COPD））的发病机制中起关键作用。然而，香烟烟雾如何直接影响系统性CD 8 + T细胞和调节性T细胞（Treg）亚群，特别是通过调节毒蕈碱乙酰胆碱受体（MR），尚未得到很好的阐明。采用流式细胞术检测健康非吸烟者（n = 15）、健康吸烟者（n = 15）和COPD患者（n = 18）与抗CD 3、抗CD 8、抗CD 25、抗Foxp 3抗体孵育后的循环CD 8 + Tc/Tc。将来自健康非吸烟者的外周血T细胞（PBT细胞）在单独的香烟烟雾提取物（CSE）或与MR激动剂/拮抗剂组合的香烟烟雾提取物（CSE）存在下培养5天。使用Ki-67/Annexin-V抗体通过流式细胞术评估增殖和凋亡，以测量CSE对CD 8 + Tc/TcB存活的影响。虽然COPD患者的CD 8 + T细胞循环百分比升高，但健康吸烟者的CD 8 + T细胞频率更高。COPD患者CD 8 + T细胞百分比升高与FEV 1下降呈负相关。CSE可促进CD 8 + T细胞的增殖，抑制其凋亡，同时促进CD 8 + T细胞的增殖和凋亡。值得注意的是，CSE对CD 8 + Tc/Tc的影响主要可以分别由毒蕈碱和阿托品（MR激动剂和拮抗剂）模拟或减弱。而毒蕈碱和阿托品均不影响CD 8 + T细胞凋亡。结果表明，吸烟可能促进吸烟者的促炎状态，这部分是由MR功能障碍介导的。MR拮抗剂可能是香烟烟雾诱导的慢性气道炎症的有益候选药物。
CD8+ T cells (Cytotoxic T cells, Tc) are known to play a critical role in the pathogenesis of smoking related airway inflammation including chronic obstructive pulmonary disease (COPD). However, how cigarette smoke directly impacts systematic CD8+ T cell and regulatory T cell (Treg) subsets, especially by modulating muscarinic acetylcholine receptors (MRs), has yet to be well elucidated. Circulating CD8+ Tc/Tregs in healthy nonsmokers (n = 15), healthy smokers (n = 15) and COPD patients (n = 18) were evaluated by flow cytometry after incubating with anti-CD3, anti-CD8, anti-CD25, anti-Foxp3 antibodies. Peripheral blood T cells (PBT cells) from healthy nonsmokers were cultured in the presence of cigarette smoke extract (CSE) alone or combined with MRs agonist/antagonist for 5 days. Proliferation and apoptosis were evaluated by flow cytometry using Ki-67/Annexin-V antibodies to measure the effects of CSE on the survival of CD8+ Tc/Tregs. While COPD patients have elevated circulating percentage of CD8+ T cells, healthy smokers have higher frequency of CD8+ Tregs. Elevated percentages of CD8+ T cells correlated inversely with declined FEV1 in COPD. CSE promoted the proliferation and inhibited the apoptosis of CD8+ T cells, while facilitated both the proliferation and apoptosis of CD8+ Tregs. Notably, the effects of CSE on CD8+ Tc/Tregs can be mostly simulated or attenuated by muscarine and atropine, the MR agonist and antagonist, respectively. However, neither muscarine nor atropine influenced the apoptosis of CD8+ Tregs. The results imply that cigarette smoking likely facilitates a proinflammatory state in smokers, which is partially mediated by MR dysfunction. The MR antagonist may be a beneficial drug candidate for cigarette smoke-induced chronic airway inflammation.