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Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway

Cellular & Molecular Immunology volume 14, pages 529–545 (2017)Cite this article

Abstract

CD8+ cytotoxic T lymphocyte (CTL) exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin (OVA)-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 (PD-1) and lymphocyte-activation gene-3 (LAG-3) and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-γ production and cytolytic effects. Naive CD8+ T cells upregulated inhibitory PD-ligand 1 (PD-L1), B- and T-lymphocyte attenuator and T-cell anergy-associated molecules (Grail and Itch) while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with (i) the upregulation of a marker for CTL functionality, diacetylated histone-H3 (diAcH3), (ii) a fourfold increase in CTLs, occurring independent of host DCs or CD4+ T cells, and (iii) the restoration of CTL IFN-γ production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, eIF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo-induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus (HIV-1) infection.

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Acknowledgements

We thank Mark Boyd for help in flow cytometric analyses. This work was supported by a Canadian Institute of Health Research (CIHR) grant (OCH 126276).

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Authors and Affiliations

  1. Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, S7N4H4, Saskatchewan, Canada

    Rong Wang, Aizhang Xu, Xueying Zhang, Jie Wu & Jim Xiang

  2. School of Public Health, University of Saskatchewan, Saskatoon, S7N 5E5, Saskatchewan, Canada

    Rong Wang, Xueying Zhang & Jim Xiang

  3. Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, S7N 5E5, Saskatchewan, Canada

    Andrew Freywald

  4. Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China

    Jianqing Xu

  5. Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, S7N 5E5, Saskatchewan, Canada

    Jim Xiang

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Wang, R., Xu, A., Zhang, X. et al. Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway. Cell Mol Immunol 14, 529–545 (2017). https://doi.org/10.1038/cmi.2016.23

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