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

• Published in: Cellular & molecular immunology Vol. 14; no. 6; pp. 529 - 545
• Main Authors: Wang, Rong, Xu, Aizhang, Zhang, Xueying, Wu, Jie, Freywald, Andrew, Xu, Jianqing, Xiang, Jim
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group
• Subjects: AKT protein; Anergy; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; CD223 antigen; CD4 antigen; CD40 Ligand - metabolism; CD40L; CD40L protein; CD8 antigen; CD8 Antigens - metabolism; Cell activation; Cell death; Cell proliferation; Chronic Disease; Chronic infection; Clonal Anergy; CTLs; Cytotoxicity; Exosomes - metabolism; Gag protein; Histones; HIV; Human immunodeficiency virus; Humans; Immunology; Infections; Infectious diseases; Initiation factor eIF-4E; Interferon; Lymphocyte Activation; Lymphocytes; Lymphocytes B; Lymphocytes T; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medical Microbiology; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbiology; Neoplasms, Experimental - immunology; Ovalbumin; PD-1 protein; PD-L1 protein; Rapamycin; research-article; Signal Transduction; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; T细胞; Vaccine; Vaccines; Viral Vaccines - immunology; Virus Diseases - immunology; γ-Interferon; 信号通路; 慢性感染; 疫苗; 细胞毒性T淋巴细胞; 衰竭; CTL exhaustion; chronic infection; CD40L signaling; anti-CD40 Ab; mTORC1 pathway; therapeutic T-cell vaccine; T-cell anergy; HIV Gag
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2016.23

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-7 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-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E 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.