Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-Infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model
Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-Infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model
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DOI：
10.1128/jvi.78.8.3827-3836.2004
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发表时间：
2004-04-01
影响因子：
5.4
通讯作者：
Kannagi, M
中科院分区：
文献类型：
--
作者：
Nomura, M;Ohashi, T;Kannagi, M
人类T细胞白血病病毒1型（HTLV-1）导致成人T细胞白血病（ATL）。尽管病毒反式激活因子Tax具有明显的转化能力，但Tax在ATL发育中的确切功能尚不清楚。为了了解Tax在ATL发展中的作用，我们在大鼠HTLV-1感染的T细胞系中引入了针对Tax的短干扰RNA（siRNA）。我们的结果表明，表达靶向Tax的siRNA成功下调Tax的表达。Tax表达的抑制与HTLV-1感染的T细胞对Tax特异性细胞毒性T淋巴细胞杀伤的抗性相关。这可能是由于Tax表达降低的直接作用，因为Tax siRNA不改变MHC-1、CD 80或CD 86的表达。此外，Tax下调的T细胞似乎失去了在T细胞缺陷的裸鼠中发展肿瘤的能力，其中亲代HTLV-1感染的细胞诱导ATL样淋巴增生性疾病。这些结果表明Tax对于激活宿主针对病毒的免疫反应和维持受感染细胞体内生长能力的重要性。我们的研究结果提供了深入了解宿主免疫系统如何在ATL发病前的长潜伏期内调查和抑制HTLV-1感染细胞生长的机制。
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-1, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.