HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling
HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling
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DOI：
10.1073/pnas.1922884117
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发表时间：
2020-06-16
影响因子：
11.1
通讯作者：
Matsuoka, Masao
中科院分区：
文献类型：
--
作者：
Higuchi, Yusuke;Yasunaga, Jun-ichirou;Matsuoka, Masao
人类T细胞白血病病毒1型（HTLV-1）是一种T细胞肿瘤和几种炎症性疾病的病原。HTLV-1 bZIP因子（HBZ）在转基因小鼠中诱导表达foxp3的致病性T细胞，引发全身性炎症和T细胞淋巴瘤，提示其在HTLV-1相关疾病中的意义。在这里，我们显示，出乎意料的是，促炎细胞因子，IL-6，抵消hbz介导的发病机制。IL-6的缺失加速了HBZ转基因小鼠的炎症和淋巴瘤形成。IL-6天生抑制调节性T细胞分化，表明IL-6可抑制hbz相关并发症。HBZ上调免疫抑制细胞因子IL-10的表达。IL-10仅在HBZ存在时才促进T细胞增殖。HBZ作为IL-10促进生长的一种机制，与STAT1和STAT3相互作用，调节IL-10/JAK/STAT信号通路。这些发现表明HTLV-1通过劫持调节性T细胞分化机制来促进受感染T细胞的增殖。HBZ诱导的IL-10可能抑制宿主免疫反应，同时促进HTLV-1感染T细胞的增殖。
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a T cell neoplasm and several inflammatory diseases. A viral gene, HTLV-1 bZIP factor (HBZ), induces pathogenic Foxp3-expressing T cells and triggers systemic inflammation and T cell lymphoma in transgenic mice, indicating its significance in HTLV-1-associated diseases. Here we show that, unexpectedly, a proinflammatory cytokine, IL-6, counteracts HBZ-mediated pathogenesis. Loss of IL-6 accelerates inflammation and lymphomagenesis in HBZ transgenic mice. IL-6 innately inhibits regulatory T cell differentiation, suggesting that IL-6 functions as a suppressor against HBZ-associated complications. HBZ up-regulates expression of the immunosuppressive cytokine IL-10. IL-10 promotes T cell proliferation only in the presence of HBZ. As a mechanism of growth promotion by IL-10, HBZ interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway. These findings suggest that HTLV-1 promotes the proliferation of infected T cells by hijacking the machinery of regulatory T cell differentiation. IL-10 induced by HBZ likely suppresses the host immune response and concurrently promotes the proliferation of HTLV-1 infected T cells.