HTLV-1 bZIP Factor Induces Inflammation through Labile Foxp3 Expression

Human T-cell leukemia virus type 1 (HTLV-1) causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg) cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4+Foxp3+ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg) cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ). In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4+ T cells were enhanced in these mice. Foxp3−CD4+ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3−T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4+ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.

人类T细胞白血病病毒1型（Human T-cell leukemia virus type 1, HTLV-1）可引发肿瘤性疾病与炎症性疾病，其中包括HTLV-1相关性脊髓病/热带痉挛性截瘫（HTLV-1-associated myelopathy/tropical spastic paraparesis, HAM/TSP）。HTLV-1碱性亮氨酸拉链因子（HTLV-1 basic leucine zipper factor, HBZ）基因编码于前病毒DNA的负链，在感染细胞与成人T细胞白血病（Adult T-cell leukemia, ATL）细胞中呈组成型表达。HBZ通过诱导Foxp3基因的转录，增加调节性T（regulatory T, Treg）细胞的数量。近期研究表明，部分CD4+Foxp3+ T细胞并非终末分化状态，而是具有向其他T细胞亚群转化的可塑性。诱导性调节性T（induced Treg, iTreg）细胞往往会丢失Foxp3的表达，并可能获得效应细胞表型，同时伴随炎性细胞因子的产生，例如干扰素-γ（interferon-γ, IFN-γ）。本研究聚焦HBZ与Foxp3，分析了HTLV-1感染相关慢性炎症的致病机制。在HBZ转基因（HBZ-transgenic, HBZ-Tg）小鼠的皮肤、肺与肠道中均观察到淋巴细胞浸润。就其机制而言，表达HBZ的CD4+ T细胞的黏附与迁移能力在该类小鼠中得到增强。与非转基因小鼠的同类细胞相比，Foxp3−CD4+ T细胞可产生更多的IFN-γ。来自HBZ-Tg小鼠与HAM/TSP患者的Treg细胞中，Helios的表达水平均有所降低，这表明诱导性调节性T细胞（iTreg）为主要的亚群。与之相符的是，HBZ-Tg小鼠Treg细胞中Foxp3基因的保守非编码序列2（conserved non-coding sequence 2, CNS2）区域呈高甲基化状态，这正是iTreg细胞的特征之一。进一步研究发现，HBZ转基因小鼠脾脏中的Treg细胞往往会丢失Foxp3的表达并产生过量的IFN-γ，而胸腺中的天然调节性T（natural Treg, nTreg）细胞的Foxp3表达则保持稳定。HBZ可促进诱导性调节性T细胞的生成，这类细胞可能会转化为分泌IFN-γ的Foxp3− T细胞。HBZ介导的CD4+ T细胞促炎表型，与HTLV-1相关性炎症的发病机制密切相关。