CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells.
CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells.
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DOI：
10.1371/journal.pone.0085191
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Garcia-Cozar F
中科院分区：
文献类型：
--
作者：
Fernandez-Ponce C;Dominguez-Villar M;Aguado E;Garcia-Cozar F
适应性 T 细胞反应对于控制 HCV 感染至关重要。虽然有临床证据表明调节性 T 细胞在慢性 HCV 感染患者中具有相关作用，因为调节性 T 细胞的数量和功能有所增加；这种现象背后的机制仍然知之甚少。越来越多的证据表明，丙型肝炎病毒的蛋白质可以抑制宿主的免疫反应。我们和其他人已经证明，HCV 存在于慢性感染患者的 CD4+ 淋巴细胞中，并且 HCV 核心蛋白会诱导 CD4+ 肿瘤细胞系 Jurkat 处于无反应状态。在这里，我们表明，用 HCV 核心慢病毒转导的 CD4+ 原代 T 细胞不仅获得无反应表型，而且还抑制旁观者 CD4+ 或 CD8+ T 细胞响应抗 CD3 和抗 CD28 刺激而产生 IL-2 和增殖。核心转导的 CD4+ T 细胞表现出的表型特征是调节性细胞因子 IL-10 的基础分泌增加、刺激后 IFN-γ 的产生减少以及调节性 T 细胞标记物 CTLA-4 和 Foxp3 的表达。还观察到具有耗尽表型的 CD4+CD25+CD127lowPD-1highTIM-3high 调节性 T 细胞的显着诱导。此外，表达 HCV 核心的 CD4+ T 细胞中 CCR7 表达降低，解释了它们在发炎组织（如受感染的肝脏）中的隔离。这项工作为由单一病毒蛋白的表达诱导的外周调节性 CD4+ T 细胞的从头生成提供了新的视角。
Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.
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DOI：
10.1084/jem.20050121
发表时间：
2005-06-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cox AL;Mosbruger T;Mao Q;Liu Z;Wang XH;Yang HC;Sidney J;Sette A;Pardoll D;Thomas DL;Ray SC
通讯作者：
Ray SC
影响因子：
5.5
作者：
Dominguez-Villar, M.;Munoz-Suano, A.;Garcia-Cozar, F.
通讯作者：
Garcia-Cozar, F.
影响因子：
5.4
作者：
Claassen, Mark A. A.;de Knegt, Robert J.;Boonstra, Andre
通讯作者：
Boonstra, Andre
影响因子：
6.4
作者：
Blackard, JT;Smeaton, L;Chung, RT
通讯作者：
Chung, RT
影响因子：
5.4
作者：
Bergqvist, A;Rice, CM
通讯作者：
Rice, CM