Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus
Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus
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DOI：
10.1128/jvi.79.18.11925-11934.2005
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Fujii, M
中科院分区：
文献类型：
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作者：
Niinuma, A;Higuchi, M;Fujii, M
人类t细胞白血病病毒1型（HTLV-1）与成人t细胞白血病相关，而HTLV-2与成人t细胞白血病无关。我们在人T细胞系（Jurkat）中发现HTLV-2 Tax2蛋白通过活化T细胞的核因子（NFAT）刺激白细胞介素(IL)-2启动子调控的报告基因表达。然而，HTLV-1 Tax1的活性在该系统中最低。HTLV-2而非HTLV-1永生化的t细胞系组成性地在细胞核中表现出活化的NFAT，并组成性地表达IL-2 mRNA。环孢素A是一种NFAT激活抑制剂，可消除htlv -2永生化t细胞系中IL-2 mRNA的诱导，同时抑制细胞生长。这种生长抑制通过在培养物中添加IL-2来恢复。此外，抗il -2受体抗体显著降低htlv -2感染的t细胞系的增殖，但对htlv -1感染的细胞没有影响。我们的研究结果表明，Tax2激活了一个通过NFAT介导的IL-2自分泌环，支持htlv -2感染细胞在低IL-2条件下的生长。这种机制在体内尤其重要，这种自分泌机制建立了非白血病性终身HTLV-2感染。结果还表明，HTLV-1和HTLV-2感染之间长期细胞因子产生的差异是致病机制差异的另一个因素。
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia. We found that HTLV-2 Tax2 protein stimulated reporter gene expression regulated by the interleukin (IL)-2 promoter through the nuclear factor of activated T cells (NFAT) in a human T-cell line (Jurkat). However, the activity of HTLV-1 Tax1 was minimal in this system. T-cell lines immortalized by HTLV-2 but not HTLV-1 constitutively exhibited activated NFAT in the nucleus and constitutively expressed IL-2 mRNA. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. This growth inhibition was rescued by the addition of IL-2 to the culture. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells. Our results suggest that Tax2 activates an IL-2 autocrine loop mediated through NFAT that supports the growth of HTLV-2-infected cells under low-IL-2 conditions. This mechanism would be especially important in vivo, where this autocrine mechanism establishes a non-leukemogenic life-long HTLV-2 infection. The results also suggest that differences in long-term cytokine production between HTLV-1 and HTLV-2 infection are another factor for the differences in pathogenesis.