转基因il -21工程T细胞疫苗通过激活mTORC1途径在慢性感染中有效转化CTL衰竭

Aizhang Xu, Xueying Zhang, R. Chibbar, A. Freywald, S. Tikoo, C. Zheng, J. Xiang
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引用次数: 3

摘要

CD8+细胞毒性T淋巴细胞(CTL)耗竭是影响慢性传染病病毒控制效果的主要障碍之一。我们之前制作了新的卵清蛋白(OVA)特异性表达OVA- texo和人类免疫缺陷病毒(HIV-1) gag -特异性Gag-TEXO疫苗,在野生型C57BL/6 (B6)小鼠中诱导治疗性免疫,并在慢性感染的重组OVA特异性腺病毒AdVOVA-B6 (AdVOVA-B6)小鼠中转化CTL衰竭。IL-21细胞因子在慢性感染的控制中起重要作用。因此,本研究构建了表达IL-21的重组转基因AdVIL-21,并通过不含转基因的AdVIL-21或对照AdVNull感染OVA-TEXO和Gag-TEXO细胞,制备了表达IL-21的OVA-TEXO/IL-21和Gag-TEXO/ IL-21疫苗,或对照疫苗(OVA-TEXO/Null和Gag-TEXO/Null),并对B6或AdVOVA-B6小鼠进行了效果评价。我们证明OVA-TEXO/IL-21和对照OVA-TEXO/Null疫苗都能够在慢性感染中转化CTL衰竭。然而,在慢性感染的AdVOVA-B6小鼠中,OVA-TEXO/IL-21疫苗通过增加更强的CTL增殖和效应细胞因子IFN-γ的表达,比对照OVA-TEXO/Null疫苗更有效地拯救耗尽的CTL,尽管这两种疫苗在野生型B6小鼠中刺激了类似的ova特异性CTL反应和对表达ova的BL6-10OVA黑色素瘤肺转移的保护性免疫。在体内,OVA-TEXO/ il -21刺激的ctl比OVA-TEXO/ null刺激的ctl更有效地上调mTORC1控制的EIF4E的磷酸化和mTORC1调节的T-bet分子的表达。重要的是,在慢性感染中,Gag-TEXO/IL21疫苗对已建立的表达gag的BL6-10Gag黑色素瘤肺转移具有比对照Gag-TEXO/Null疫苗更强的gag特异性治疗免疫。因此,这项研究应该对开发用于慢性感染患者的新型治疗性疫苗产生重大影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection
CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.
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