Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells
Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells
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DOI：
10.4049/jimmunol.169.6.3120
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发表时间：
2002-09-15
影响因子：
4.4
通讯作者：
Hiscott, J
中科院分区：
文献类型：
--
作者：
Sharma, S;Grandvaux, N;Hiscott, J
IFN调节因子(IRF)-4是IRF转录因子家族中淋巴/髓性受限的成员，在成熟淋巴细胞的稳态和功能中起重要作用。IRF-4的表达在静息的原代T细胞中受到严格调控，并在被TCR交联或磷酯和钙离子载体（PMA/离子霉素）等模拟ag刺激激活后，在mRNA和蛋白水平上被短暂诱导。然而，IRF-4在人类T细胞白血病病毒I型（HTLV-I）感染的T细胞中组成性上调，作为htv -I Tax癌蛋白的直接基因靶点。在这项研究中，我们证明了htlv - 1感染的T淋巴细胞中的慢性IRF-4表达与白血病表型相关，我们研究了htlv - 1转化的T细胞中连续产生IRF-4的机制。htlv -1感染细胞中的IRF-4表达是通过激活NF-kappaB和NF-AT途径驱动的，导致p50、p65和c-Rel与kappaB1元件结合，p50、c-Rel和NF-ATp与IRF-4启动子-617至-209区域内的CD28RE元件结合。此外，kappaB1或CD28RE位点的突变可阻断T细胞中税收介导的人IRF-4启动子的转激活。这些实验首次详细分析了HTLV-I感染和CD4(+) T淋巴细胞转化背景下的人类IRF-4转录调控。
IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However-, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTIV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes.