Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes
Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes
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DOI：
10.1159/000369719
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Zeng, Qiutang
中科院分区：
文献类型：
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作者：
Liu, Yuzhou;Zhao, Xiaoqi;Zeng, Qiutang
工作背景：越来越多的证据表明，病理性自身反应性免疫反应是导致斑块破裂和随后急性冠状动脉综合征（ACS）发病的原因。天然存在的CD4（+）CD25（+）调节性T细胞（nTcells）在抑制病理性自身反应性免疫应答和维持免疫稳态中是不可或缺的。但ACS患者糖蛋白A重复占优势（GARP）（+）CD4（+）CD25（+）激活的nT细胞数量和抑制功能受损。最近的研究表明血红素氧合酶-1（HO-1）可以通过促进Foxp3的表达来调节获得性免疫反应。因此，我们推测HO-1可能增强ACS患者GARP（+）CD4（+）CD25（+）T细胞的功能，从而调节免疫失衡。方法：分离健康志愿者（对照组，n = 30）、稳定型心绞痛（SA，n = 40）和急性冠脉综合征（ACS，n = 51）患者的T淋巴细胞。这些细胞中的一半用HO-1诱导剂（氯化血红素）处理48小时，另一半用完全RPMI-1640培养基孵育。采用流式细胞术检测体外刺激后T辅助细胞1（Th1）、Th2、Th17和潜伏相关肽（LTP）（+）CD4（+）T细胞的频率以及CD4（+）CD25（+）T细胞Foxp3和GARP的表达。通过胸苷摄取来测量活化的TdR的抑制功能。采用酶联免疫吸附试验（ELISA）测定血浆中转化生长因子-1（TGF-β 1）的水平。通过实时聚合酶链反应分析编码这些蛋白质的基因的表达水平。结果如下：与SA组和对照组相比，ACS患者表现出GARP + CD4（+）CD25（+）T细胞的数量和抑制功能受损，以及混合的Th1/Th17-优势T细胞应答。ACS患者的T细胞中CD14的表达也低于SA患者和对照个体。用HO-1诱导剂处理增强了GARP + CD4（+）CD25（+）T淋巴细胞的生物活性，并导致活化T细胞表达GARP和GARP增加。结论：GARP + CD4（+）CD25（+）T细胞的数量减少和抑制功能受损导致效应T细胞过度增殖，导致斑块不稳定和ACS的发作。HO-1通过促进ACS患者活化T细胞上GARP和GARP的表达，有效地恢复受损的GARP + CD4（+）CD25（+）T细胞。版权所有（C）2015 S. Karger AG，巴塞尔
Background: Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4(+)CD25(+)regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP)(+)CD4(+)CD25(+) activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP(+) CD4(+) CD25(+)Tregs in patients with ACS and thus regulate immune imbalance. Methods: T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) (+)CD4(+) T cells and the expression of Foxp3 and GARP by CD4(+)CD25(+)T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-beta 1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Results: Patients with ACS exhibited an impaired number and suppressive function of GARP+ CD4(+) CD25(+)Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP+ CD4(+) CD25(+)Tregs and resulted in increased expression of LAP and GARP by activated T cells. Conclusions: The reduced number and impaired suppressive function of GARP+ CD4(+) CD25(+)Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP+ CD4(+) CD25(+)Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells. Copyright (C) 2015 S. Karger AG, Basel