An engineered novel lentivector specifically transducing dendritic cells and eliciting robust HBV-specific CTL response by upregulating autophagy in T cells

Abstract

Dendritic cells (DCs) play a predominant role in initiating cell immune responses. Here we generated a DC-targeting lentiviral vector (LVDC-UbHBcAg-LIGHT) and evaluated its capacity to elicit HBV-specific cytotoxic T lymphocyte (CTL) responses. DC-SIGN-mediated specific transduction using this construct was confirmed in DC-SIGN-expressing 293T cells and ex vivo-cultured bone marrow cells. LVDC-UbHBcAg-LIGHT-loaded DCs were highly effective in inducing HBV-specific CTLs. Mechanistic studies demonstrated autophagy blocking led to a significant increase in apoptosis and obvious inhibition of CD8 + T cells entry into S-phase, correspondingly attenuated LVDC-UbHBcAg-LIGHT-loaded DC-induced T cell responses. This observation was supported by accumulation of pro-apoptotic proteins and the main negative cell cycle regulator-CDKN1B that otherwise would be degraded in activated T cells where autophagy preferentially occured. Our findings revealed an important role of autophagy in the activation of T cells and suggested LVDC-UbHBcAg-LIGHT may potentially be used as a therapeutic strategy to combat persistent HBV infection with higher security.

Combined therapy with methotrexate nanoconjugate and dendritic cells with downregulated IL-10R expression modulates the tumor microenvironment and enhances the systemic anti-tumor immune response in MC38 murine colon carcinoma

“…Similar observations were found in cells transduced with the control shRNA sequence (DC/shN/TAg) and should be explained by the immunogenicity of lentiviral vectors. Our observations are in line with the research of others indicating an elevated expression of these surface molecules on the DCs after lentiviral transduction ( 43 , 44 ). Moreover, Breckpot et al.…”

“…Similar observations were found in cells transduced with the control shRNA sequence (DC/shN/TAg) and should be explained by the immunogenicity of lentiviral vectors. Our observations are in line with the research of others indicating an elevated expression of these surface molecules on the DCs after lentiviral transduction (43,44). Moreover, Breckpot et al demonstrated that myeloid DCs recognize lentiviral antigens through TLR3 and TLR7 toll-like receptors, which leads not only to increased expression of MHC II and costimulatory molecules but also enhanced IFN-b production by these cells (44).…”

A pan-cancer analysis for the oncogenic role of cyclin-dependent kinase inhibitor 1B in human cancers

“…Research is mounting that CDKN1B alterations are crucial in the development and prognosis of malignancies [32][33] . The samples from ovarian cancer, testicular cancer, and uterine carcinosarcoma revealed that "ampli cation" was the most prevalent kind of mutation.…”

Interplay between Cellular Autophagy and Hepatitis B Virus Replication: A Systematic Review

“…Ma et al constructed a DC directed against a lentivector (LV) (LVDC-UbHBcAg-LIGHT) for use as a potential vaccine to induce anti-HBV immune responses. They found that the vaccine elicited effective anti-HBV effects in HBV transgenic mice [68,69]. Further study revealed that the increased autophagy of T cells primarily contributed to the elimination of HBVs.…”

“…Autophagy is essential for HBV-specific adaptive immune responses. Ma et al demonstrated the ability of a lentivector-targeting engineered dendritic cell (DC) to induce robust T-cell responses and elicit effective anti-HBV effect in HBV transgenic mice [68,69]. They further revealed that the upregulation of the autophagy of T cells aids in the eradication of HBV by promoting the survival and proliferation of activated CD8 + T cells.…”