Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-Infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells
Tax-inducible production of CC chemokine ligand 22 by human T cell leukemia virus type 1 (HTLV-1)-Infected T cells promotes preferential transmission of HTLV-1 to CCR4-expressing CD4+ T cells
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DOI：
10.4049/jimmunol.180.2.931
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Yoshie, Osamu
中科院分区：
文献类型：
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作者：
Hieshima, Kunio;Nagakubo, Daisuke;Yoshie, Osamu
成人T细胞白血病是一种成熟的CD4(+)T细胞恶性肿瘤，主要表达CCR4，在病因学上与人类T细胞白血病病毒1型(HTLV-1)有关。由于HTLV-1的传播依赖于密切的细胞间接触，HTLV-1感染的T细胞可能优先与CCR4(+)CD4(+)T细胞相互作用，以实现有效的病毒传播。在基因表达和蛋白分泌方面，我们发现HTLV-1Tax癌蛋白与CCR4配体CCL22在HTLV-1感染的T细胞中具有很强的相关性。在HTLV-1阴性的T细胞系中瞬时表达Tax激活了CCL22启动子并诱导了CCL22。此外，被小干扰RNA敲除的Tax基因降低了感染T细胞中CCL22的表达。这些发现表明，CCL22是一个与Tax有关的细胞靶基因。在趋化实验中，HTLV-1感染的T细胞培养上清液选择性地吸引PBMC中CCR4(+)的CD4(+)T细胞。这一作用可通过用抗CCL22抗体或用合成的CCR4拮抗剂处理PBMC来阻断。在共培养实验中，原代CCR4(+)CD4(+)T细胞与表达Tax的细胞显著黏附。这种黏附可被CCR4拮抗剂或百日咳毒素阻断。有趣的是，CCR4被重新分配到接触区，在某些情况下，这伴随着被感染的T细胞中一个极化的微管组织中心，这是病毒学突触形成的指标。最后，在与HTLV-1产生细胞的共培养实验中，抗CCL22抗体治疗也阻断了HTLV-1向原代CD4(+)T细胞的传播。因此，HTLV-1感染的T细胞通过Tax产生CCL22，并选择性地与CCR4(+)CD4(+)T细胞相互作用，导致HTLV-1优先传递给CCR4(+)CD4(+)T细胞。
Adult T cell leukemia is a mature CD4(+) T cell malignancy which predominantly expresses CCR4 and is etiologically associated with human T cell leukemia virus type 1 (HTLV-1). Because HTLV-1 transmission depends on close cell-cell contacts, HTLV-1-infected T cells may preferentially interact with CCR4(+)CD4(+) T cells for efficient viral transmission. In terms of gene expression and protein secretion, we found a strong correlation between HTLV-1 Tax oncoprotein and CCL22, a CCR4 ligand, in HTLV-1-infected T cells. Transient Tax expression in an HTLV-1-negative T cell line activated the CCL22 promoter and induced CCL22. Additionally, tax gene knockdown by small interference RNA reduced CCL22 expression in the infected T cells. These findings indicate that CCL22 is a cellular target gene of Tax. In chemotaxis assays, the culture supernatants of HTLV-1-infected T cells selectively attracted CCR4(+)CD4(+) T cells in PBMCs. This was blocked by pretreating the supernatants with anti-CCL22 Ab or PBMCs with a synthetic CCR4 antagonist. In coculture experiments, primary CCR4(+)CD4(+) T cells significantly adhered to Tax-expressing cells. This adhesion was blocked by the CCR4 antagonist or pertussis toxin. Interestingly, CCR4 was redistributed to the contact region, and in some cases, this was accompanied by a polarized microtubule-organizing center, which is an indicator of virological synapse formation, in the infected T cells. Finally, anti-CCL22 Ab treatment also blocked HTLV-1 transmission to primary CD4(+) T cells in coculture experiments with HTLV-1 producer cells. Thus, HTLV-1-infected T cells produce CCL22 through Tax and selectively interact with CCR4(+)CD4(+) T cells, resulting in preferential transmission of HTLV-1 to CCR4(+)CD4(+) T cells.