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《中国免疫学杂志（英文版）》
>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
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 C57BLJ6 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,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.
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