An engineered novel lentivector specifically transducing dendritic cells and eliciting robust HBV-specific CTL response by upregulating autophagy in T cells
An engineered novel lentivector specifically transducing dendritic cells and eliciting robust HBV-specific CTL response by upregulating autophagy in T cells
复制标题
一种工程化的新型慢载体，特异性转导树突状细胞，并通过上调 T 细胞中的自噬来引发强大的 HBV 特异性 CTL 反应
DOI：
10.1080/15384101.2018.1471312
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Tang, Zhenghao
中科院分区：
文献类型：
--
作者：
Ma, Siyuan;Chen, Xiaohua;Tang, Zhenghao
摘要树突状细胞（Dendritic cells，DC）在启动细胞免疫应答中起主要作用。在这里，我们产生了DC靶向慢病毒载体（LVDC-UbHBcAg-LIGHT），并评估其引发HBV特异性细胞毒性T淋巴细胞（CTL）反应的能力。在表达DC-SIGN的293 T细胞和离体培养的骨髓细胞中证实了使用该构建体的DC-SIGN介导的特异性转导。LVDC-UbHBcAg-LIGHT负载的DC在诱导HBV特异性CTL方面非常有效。机制研究表明，自噬阻断导致凋亡显著增加，明显抑制CD 8 + T细胞进入S期，相应地减弱LVDC-UbHBcAg-LIGHT负载DC诱导的T细胞应答。这一观察结果得到了促凋亡蛋白和主要负细胞周期调节因子CDKN 1B的积累的支持，否则这些蛋白和因子将在自噬优先发生的活化T细胞中降解。我们的研究结果揭示了自噬在T细胞活化中的重要作用，并表明LVDC-UbHBcAg-LIGHT可能被用作一种治疗策略，以更高的安全性对抗持续的HBV感染。
ABSTRACT Dendritic cells (DCs) play a predominant role in initiating cell immune responses. Here we generated a DC-targeting lentiviral vector (LVDC-UbHBcAg-LIGHT) and evaluated its capacity to elicit HBV-specific cytotoxic T lymphocyte (CTL) responses. DC-SIGN-mediated specific transduction using this construct was confirmed in DC-SIGN-expressing 293T cells and ex vivo-cultured bone marrow cells. LVDC-UbHBcAg-LIGHT-loaded DCs were highly effective in inducing HBV-specific CTLs. Mechanistic studies demonstrated autophagy blocking led to a significant increase in apoptosis and obvious inhibition of CD8 + T cells entry into S-phase, correspondingly attenuated LVDC-UbHBcAg-LIGHT-loaded DC-induced T cell responses. This observation was supported by accumulation of pro-apoptotic proteins and the main negative cell cycle regulator-CDKN1B that otherwise would be degraded in activated T cells where autophagy preferentially occured. Our findings revealed an important role of autophagy in the activation of T cells and suggested LVDC-UbHBcAg-LIGHT may potentially be used as a therapeutic strategy to combat persistent HBV infection with higher security.