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.
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.
Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N4H4.|School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
Rong
R
Wang
Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N4H4.
Aizhang
A
Xu
Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N4H4.|School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
Xueying
X
Zhang
Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N4H4.
Jie
J
Wu
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
Andrew
A
Freywald
Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
Jianqing
J
Xu
Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N4H4.|School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.|Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
Jim
J
Xiang
D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002908:Chronic Disease; D017635:Clonal Anergy; D055354:Exosomes / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology*
D016827:CD8 Antigens; D014765:Viral Vaccines; D023201:CD40 Ligand; D000076222:Mechanistic Target of Rapamycin Complex 1