Author(s)

Aizhang Xu^1,2*, Xueying Zhang^1,2*, Rajni Chibbar³, Andrew Freywald³, Suresh Tikoo⁴, Changyu Zheng⁵, Jim Xiang^1,2

¹Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Canada.
²Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
³Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
⁴School of Public Health, University of Saskatchewan, Saskatoon, Canada.
⁵Molecular Physiology and Therapeutic Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, USA.

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.

IL-21, Chronic Infection, CTL Exhaustion, Exosome, T Cell Vaccine

Xu, A. , Zhang, X. , Chibbar, R. , Freywald, A. , Tikoo, S. , Zheng, C. and Xiang, J. (2019) Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection. World Journal of Vaccines, 9, 1-21. doi: 10.4236/wjv.2019.91001.