Harhaj Nicole S, Janic Branislava, Ramos Juan C, Harrington William J, Harhaj Edward W
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, 1550 NW 10 Avenue, Miami, FL 33136, USA.
Virology. 2007 May 25;362(1):99-108. doi: 10.1016/j.virol.2006.12.020. Epub 2007 Jan 26.
HTLV-I infection is associated with the development of adult T cell leukemia (ATL) and the neuroinflammatory disease HAM/TSP. There are quantitative and qualitative differences in the antiviral cytotoxic T cell (CTL) response in ATL and HAM/TSP although the underlying mechanisms are unclear. Here, we demonstrate that the HTLV-I Tax trans-activating protein is a transcriptional activator of CD40 ligand (CD40L), a critical regulator of dendritic cell maturation and adaptive immunity. Tax activates CD40L expression via a cyclosporin A insensitive pathway that is also independent of NF-kappaB. Although Tax upregulates CD40L gene expression, CD40L expression is absent in Tax-expressing HTLV-I-transformed cell lines via an epigenetic mechanism involving methylation. T lymphocytes cultured ex vivo from ATL patients, but not HAM/TSP or normal controls, exhibit a potent block in the induction of CD40L, but not CD69. However, the CD40L gene is not silenced by methylation in ATL patients, thus CD40L is downregulated by distinct mechanisms in HTLV-I-transformed cell lines and ATL patients.
人类嗜T淋巴细胞病毒I型（HTLV-I）感染与成人T细胞白血病（ATL）以及神经炎性疾病HAM/TSP的发生相关。尽管潜在机制尚不清楚，但在ATL和HAM/TSP中，抗病毒细胞毒性T细胞（CTL）反应存在数量和质量上的差异。在此，我们证明HTLV-I Tax反式激活蛋白是CD40配体（CD40L）的转录激活因子，CD40L是树突状细胞成熟和适应性免疫的关键调节因子。Tax通过一种对环孢菌素A不敏感且独立于核因子κB的途径激活CD40L表达。虽然Tax上调CD40L基因表达，但通过涉及甲基化的表观遗传机制，在表达Tax的HTLV-I转化细胞系中不存在CD40L表达。从ATL患者而非HAM/TSP患者或正常对照者体外培养的T淋巴细胞，在诱导CD40L方面表现出强烈阻滞，但对CD69的诱导无此现象。然而，在ATL患者中CD40L基因并未因甲基化而沉默，因此在HTLV-I转化细胞系和ATL患者中，CD40L通过不同机制被下调。
