Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes
Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes
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DOI：
10.1002/eji.200324251
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发表时间：
2003-12-01
影响因子：
5.4
通讯作者：
Mills, KHG
中科院分区：
文献类型：
--
作者：
Brady, MT;MacDonald, AJ;Mills, KHG
尽管存在HCV特异性细胞和体液免疫应答，但大多数丙型肝炎病毒（HCV）感染变为慢性。我们以前曾提出，IL-10分泌抗原特异性调节性T细胞可能有助于病毒的持久性，并证明在这里，从慢性HCV感染患者的外周血单核细胞（PBMC）分泌IL-10，但不是IFN-γ，在响应HCV非结构蛋白4（NS 4）。中和性抗IL-10抗体在体外恢复了这种有缺陷的抗原特异性IFN-γ产生。此外，来自正常个体的PBMC响应于NS 4而分泌IL-10，这表明在HCV感染患者中，除了T细胞之外，先天免疫系统的细胞也产生IL-10。细胞分离实验表明，先天性IL-10由血液单核细胞产生，而不是树突状细胞（DC）。此外，NS 4抑制PBMC响应于LPS和IFN-γ的IL-12产生，以及正常个体中Th 1响应于回忆抗原。此外，NS 4刺激的单核细胞的上清液抑制LPS诱导的DC成熟，并抑制其刺激同种特异性T细胞增殖和IFN-γ产生的能力。我们的数据表明，HCV通过诱导IL-10和抑制单核细胞产生IL-12来破坏细胞免疫，这反过来又抑制了驱动Th 1细胞分化的DC的活化。
The majority of hepatitis C virus (HCV) infections become chronic, despite the presence of HCV-specific cellular and humoral immune responses. We have previously suggested that IL-10-secreting antigen-specific regulatory T cells may contribute to viral persistence, and demonstrate here that peripheral blood mononuclear cells (PBMC) from chronically HCV-infected patients secrete IL-10, but not IFN-gamma, in response to HCV nonstructural protein 4 (NS4). A neutralizing anti-IL-10 antibody restored this defective antigen-specific IFN-gamma production in vitro. Furthermore, PBMC from normal individuals secreted IL-10 in response to NS4, suggesting that cells of the innate immune system, in addition to T cells, produced IL-10 in the HCV-infected patients. Cell separation experiments revealed that the innate IL-10 was produced by blood monocytes, but not dendritic cells (DC). In addition, NS4 inhibited IL-12 production by PBMC in response to LPS and IFN-gamma, and Th1 responses to recall antigens in normal individuals. Furthermore, supernatants from NS4-stimulated monocytes inhibited LPS-induced maturation of DC and suppressed their capacity to stimulate proliferation and IFN-gamma production by allospecific T cells. Our data suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells.