Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon
Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon
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DOI：
10.1128/jvi.02564-08
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发表时间：
2009-05-15
影响因子：
5.4
通讯作者：
Kannagi, Mari
中科院分区：
文献类型：
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作者：
Kinpara, Shuichi;Hasegawa, Atsuhiko;Kannagi, Mari
人类t细胞白血病病毒1型（HTLV-1）引起成人t细胞白血病（ATL）、HTLV-1相关脊髓病/热带痉挛性截瘫和其他炎症性疾病。尽管HTLV-1感染的后果如此严重，但HTLV-1在体内的表达水平非常低，并在细胞转移到培养条件后迅速增加。这一现象的机制仍然不清楚。在本研究中，我们发现人和小鼠间质细胞，如上皮细胞和成纤维细胞，在ATL和非ATL HTLV-1感染细胞中抑制HTLV-1的表达。HTLV-1感染细胞与人上皮样细胞（HEK293T）或小鼠胚胎成纤维细胞（NIH 3T3）共培养后，HTLV-1 mRNA和蛋白水平显著降低。当感染细胞从共培养中分离出来时，病毒表达在接下来的48小时内恢复到原始水平。与HEK293T细胞共培养也抑制了原代ATL细胞在培养前24小时内自发诱导HTLV-1表达。htlv -1感染细胞与HEK293T细胞共培养诱导I型干扰素应答，通过干扰素（ifn - β）启动子激活和ifn刺激基因上调检测。hek293t介导的HTLV-1表达抑制被人ifn - α / β受体抗体部分抑制。中和小鼠ifn - β抗体可明显消除NIH 3t3介导的抑制作用。此外，当将htlv -1感染的细胞腹腔注射到野生型小鼠体内时，病毒在htlv -1感染细胞中的表达被显著抑制，而在缺乏I型IFN反应的IFN调节因子7敲除小鼠体内则没有。这些发现表明，先天免疫系统至少通过I型IFN抑制HTLV-1在体内的表达。
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis, and other inflammatory diseases. Despite such severe outcomes of HTLV-1 infection, the level of HTLV-1 expression in vivo is very low and rapidly increases after transfer of cells to culture conditions. The mechanisms of this phenomenon have remained obscure. In the present study, we found that human and mouse stromal cells, such as epithelial cells and fibroblasts, suppressed HTLV-1 expression in ATL and non-ATL HTLV-1-infected cells. HTLV-1 mRNA and proteins in HTLV-1-infected cells markedly decreased upon coculture with human epithelial-like cells (HEK293T) or mouse embryo fibroblasts (NIH 3T3). When infected cells were reisolated from the cocultures, viral expression was restored to the original level over the following 48 h. Spontaneous induction of HTLV-1 expression in primary ATL cells in the first 24 h of culture was also inhibited by coculture with HEK293T cells. Coculture of HTLV-1-infected cells and HEK293T cells induced type I interferon responses, as detected by beta interferon (IFN-beta) promoter activation and IFN-stimulated gene upregulation. HEK293T-mediated suppression of HTLV-1 expression was partly inhibited by antibodies to human IFN-alpha/beta receptor. NIH 3T3-mediated suppression was markedly abrogated by neutralizing antibodies to mouse IFN-beta. Furthermore, viral expression in HTLV-1-infected cells was significantly suppressed when the infected cells were intraperitoneally injected into wild-type mice but not IFN regulatory factor 7 knockout mice that are deficient of type I IFN responses. These findings indicate that the innate immune system suppresses HTLV-1 expression in vivo, at least through type I IFN.