Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection — Oak Academic Publishing
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Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection
Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Canada
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Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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School of Public Health, University of Saskatchewan, Saskatoon, Canada
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Molecular Physiology and Therapeutic Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, USA
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Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Canada
1 Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Canada
2 Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
3 Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
4 Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
5 School of Public Health, University of Saskatchewan, Saskatoon, Canada
6 Molecular Physiology and Therapeutic Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, USA
7 Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Canada
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 EXO and 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/Null vaccines 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/Null vaccine 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/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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