HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT).
HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT).
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DOI：
10.1371/journal.ppat.1005372
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发表时间：
2016-01
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：
Yasuma K;Yasunaga J;Takemoto K;Sugata K;Mitobe Y;Takenouchi N;Nakagawa M;Suzuki Y;Matsuoka M
人T细胞白血病病毒1型（HTLV-1）感染体内CD 4 + T细胞并诱导受感染细胞增殖，这导致在一些受感染个体中成人T细胞白血病（ATL）的发作。HTLV-1 bZIP因子（HBZ）基因编码于HTLV-1的负链中，在发病机制中起关键作用。在这项研究中，使用HBZ转导的T细胞进行的RNA-seq和ChIP-seq分析显示，除了调节性T细胞相关基因Foxp 3和Ccr 4的表达和启动子乙酰化水平外，HBZ还上调共抑制分子T细胞免疫球蛋白和ITIM结构域（TIGIT）的表达和启动子乙酰化水平。TIGIT在来自HBZ转基因（HBZ-Tg）小鼠的CD 4 + T细胞上以及在体内HTLV-1相关脊髓病/热带痉挛性轻瘫（HAM/TSP）的ATL细胞和HTLV-1感染的CD 4 + T细胞上表达。与TIGIT-CD 4 + T细胞相比，HBZ-Tg小鼠的TIGIT+ CD 4+细胞中Blimp 1和IL-10的表达上调，表明TIGIT表达与IL-10产生之间的相关性。当来自HBZ-Tg小鼠的⑶ 4 + T细胞用TIGIT的配体⑶ 155刺激时，它们的抑制性细胞因子IL-10的产生增强。此外，来自HBZ-Tg小鼠的树突状细胞在刺激后产生高水平的IL-10。这些数据表明，HBZ通过TIGIT和IL-10将免疫系统改变为抑制状态。重要的是，TIGIT在体外抑制T细胞对另一种HTLV-1病毒蛋白Tax的应答。在一些HAM/TSP患者中，TIGIT和PD-1的阻断略微增加了抗Tax T细胞活性。这些结果表明，在HTLV-1感染的细胞上HBZ诱导的TIGIT损害T细胞对病毒抗原的应答。这项研究表明，HBZ诱导的TIGIT在减弱宿主免疫应答和塑造有利于HTLV-1的微环境中起着关键作用。HTLV-1是一种嗜T细胞的潜伏感染性病毒，可引起T细胞恶性肿瘤、ATL和炎性疾病。HTLV-1逃避免疫应答并建立慢性感染的机制尚未了解。最近的研究表明，TIGIT，一种共抑制分子，在肿瘤浸润T细胞和病毒感染期间的T细胞上表达，其抑制抗肿瘤和抗病毒免疫应答。此外，阻断TIGIT和程序性细胞死亡-1（PD-1）的共抑制分子破坏免疫检查点并增强抗肿瘤活性。我们发现TIGIT被HBZ上调，并且TIGIT通过免疫抑制细胞因子IL-10损害抗病毒免疫应答。这些发现表明HTLV-1利用感染细胞上的共抑制分子来逃避宿主免疫应答。我们还发现，阻断HTLV-1感染患者外周血单核细胞上的TIGIT和PD-1增强了对病毒的免疫应答。这些发现表明HTLV-1使用诱导的TIGIT形成有利于其持久性的微环境的机制。TIGIT是ATL和HTLV-1感染患者的潜在治疗靶标。
Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT’s ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1. HTLV-1 is a T-cell-tropic, latently infectious virus that causes a T-cell malignancy, ATL, and inflammatory diseases. The mechanisms by which HTLV-1 evades the immune response and establishes chronic infection are not yet understood. Recent studies have demonstrated that TIGIT, a co-inhibitory molecule, is expressed on tumor infiltrating T cells and T cells during viral infection, which suppresses the anti-tumor and anti-viral immune responses. Furthermore, blockade of co-inhibitory molecules of TIGIT and programmed cell death-1 (PD-1) disrupts immune checkpoints and enhances anti-tumor activity. We found that TIGIT is upregulated by HBZ, and TIGIT impairs anti-virus immune responses through an immunosuppressive cytokine, IL-10. These findings show that HTLV-1 utilizes a co-inhibitory molecule on infected cells to evade the host immune responses. We also found that blocking of TIGIT and PD-1 on peripheral blood mononuclear cells in HTLV-1 infected patients enhances immune responses to virus. These findings suggest a mechanism by which HTLV-1 shapes a microenvironment favorable to its persistence using induced TIGIT. TIGIT is a potential therapeutic target for ATL and HTLV-1 infected patients.