文章基本信息

标题：Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection
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作者：Aizhang Xu ; Xueying Zhang ; Rajni Chibbar 等
期刊名称：World Journal of Vaccines
印刷版ISSN：2160-5815
电子版ISSN：2160-5823
出版年度：2019
卷号：09
期号：01
页码：1-21
DOI：10.4236/wjv.2019.91001
出版社：Scientific Research Publishing
摘要：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-T_EXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-T_EXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdV_OVA-infected B6 (AdV_OVA-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 AdV_IL-21, and generated IL-21-expressing OVA-T_EXO/IL-21 and Gag-T_EXO/IL21 vaccines, or control vaccines (OVA-T_EXO/Null and Gag-T_EXO/Null) by infecting OVA-T_EXOand Gag-T_EXO cells with AdV_IL-21 or the control AdV_Null, lacking transgene, and assessed their effects in B6 or AdV_OVA-B6 mice. We demonstrate that both OVA-T_EXO/IL-21 and control OVA-T_EXO/Nullvaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-T_EXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN- γ expression than the control OVA-T_EXO/Nullvaccine in AdV_OVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10_OVA melanoma lung metastasis in wild-type B6 mice. In vivo , the OVA-T_EXO/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-T_EXO/Null-stimulated ones. Importantly, the Gag-T_EXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10_Gag melanoma lung metastases than the control Gag-T_EXO/Nullvaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.
关键词：IL-21;Chronic Infection;CTL Exhaustion;Exosome;T Cell Vaccine