HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.
HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.
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DOI：
10.1371/journal.ppat.1001274
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发表时间：
2011-02-10
期刊：
影响因子：
6.7
通讯作者：
Matsuoka M
中科院分区：
文献类型：
--
作者：
Satou Y;Yasunaga J;Zhao T;Yoshida M;Miyazato P;Takai K;Shimizu K;Ohshima K;Green PL;Ohkura N;Yamaguchi T;Ono M;Sakaguchi S;Matsuoka M
人T细胞白血病病毒1型（HTLV-1）是CD 4 + T细胞的肿瘤性疾病、成人T细胞白血病（ATL）和炎性疾病（包括HTLV-1相关的脊髓病/热带痉挛性下肢轻瘫、皮炎和炎性肺病）的病原体。ATL细胞组成性表达CD 25，类似于CD 25 + CD 4+调节性T细胞（Treg）。大约60%的ATL病例确实含有表达FoxP 3的白血病细胞，FoxP 3是Treg细胞的关键转录因子。HTLV-1编码反义转录物HTLV-1 bZIP因子（HBZ），其在所有ATL病例中表达。在这项研究中，我们表明，转基因表达的HBZ在CD 4 + T细胞诱导T细胞淋巴瘤和全身炎症小鼠，类似于HTLV-1感染的个人中观察到的疾病。在HBZ转基因小鼠中，体内CD 4 + Foxp 3 + Treg细胞和效应/记忆CD 4 + T细胞增加。作为Treg细胞增加的机制，HBZ表达直接诱导T细胞中Foxp 3基因的转录。HBZ转基因小鼠中CD 4 + Foxp 3 + Treg细胞的增殖能力增强，但功能受损。HBZ可以与Foxp 3和NFAT物理相互作用，从而削弱Treg细胞的抑制功能。因此，HBZ在CD 4 + T细胞中的表达是HTLV-1诱导的肿瘤和炎性疾病的关键机制。人类T细胞白血病病毒1型（HTLV-1）是第一种与人类疾病相关的逆转录病毒，包括源自CD 4 + T细胞的侵袭性白血病、成人T细胞白血病（ATL）以及中枢神经系统、肺或皮肤的慢性炎性疾病。然而，HTLV-1如何诱导这些疾病仍有待阐明。病毒基因Tax被认为是HTLV-1发病机制中的关键参与者，但Tax表达经常在ATL细胞中丢失。另一种病毒基因HBZ在HTLV-1感染的细胞和ATL细胞中组成型表达。然而，HBZ如何在HTLV-1相关疾病中发挥作用仍不清楚。我们在这里表明，HBZ诱导的T细胞淋巴瘤和慢性炎症在体内类似于HTLV-1感染的个体，表明HBZ在HTLV-1相关的人类疾病中的重要作用。如在HTLV-1感染个体中观察到的，HBZ转基因小鼠中的效应/记忆和调节性CD 4 + T细胞增加。此外，HBZ可以与宿主转录因子Foxp 3和NFAT相互作用，导致Treg功能失调。由HBZ诱导的Treg失调被认为是HTLV-1发病机制的关键机制。本研究揭示了HTLV-1的相关发病机制，为人类疾病的预防和治疗提供了重要线索。
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases. Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus that is associated with human diseases including an aggressive leukemia derived from CD4+ T cells, adult T-cell leukemia (ATL), and chronic inflammatory diseases of the central nervous system, lung, or skin. However, it remains to be elucidated how HTLV-1 induces these diseases. A viral gene, tax, has been considered as a critical player in HTLV-1 pathogenesis, yet Tax expression is frequently lost in ATL cells. Another viral gene, HBZ, is constitutively expressed in both HTLV-1 infected cells and ATL cells. However, it remains unknown how HBZ functions in the HTLV-1-related diseases. We show here that the HBZ induced T-cell lymphoma and chronic inflammation in vivo similar to those in HTLV-1 infected individuals, indicating an important role of HBZ in HTLV-1 associated human diseases. As observed in HTLV-1 infected individuals, effector/memory and regulatory CD4+ T cells were increased in the HBZ-transgenic mice. Further, HBZ could interact with host transcription factors, Foxp3 and NFAT, leading to dysregulation of Treg function. The Treg dysregulation induced by HBZ is thought to be a critical mechanism of the HTLV-1 pathogenesis. This study sheds light on the HTLV-1 associated pathogenesis and provides an important clue to prevent or treat the human diseases.
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影响因子：
5.4
作者：
Jones, KS;Petrow-Sadowski, C;Ruscetti, FW
通讯作者：
Ruscetti, FW
DOI：
10.1073/pnas.192162899
发表时间：
2002-10-01
影响因子：
11.1
作者：
Lehmann, J;Huehn, J;Hamann, A
通讯作者：
Hamann, A
DOI：
10.1073/pnas.92.4.1057
发表时间：
1995-02-14
影响因子：
11.1
作者：
GROSSMAN, WJ;KIMATA, JT;RATNER, L
通讯作者：
RATNER, L
影响因子：
3.3
作者：
Gallo RC
通讯作者：
Gallo RC
DOI：
10.1016/0006-291x(89)92322-x
发表时间：
1989-09-15
影响因子：
3.1
作者：
LAROCCA, D;CHAO, LA;BRUNCK, TK
通讯作者：
BRUNCK, TK