Abstract
CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.
Highlights
During acute viral infections, both innate and adaptive immunity work together contribute to the clearance of the pathogens [1]
In this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting cytotoxic T lymphocyte (CTL) exhaustion in chronic infection
The inhibitory PD-1 molecule was originally found on active T cells following T cell receptor (TCR) engagement and became a T cell-intrinsic mechanism for negatively regulating CTL responses [38] [39]
Summary
Both innate and adaptive immunity work together contribute to the clearance of the pathogens [1]. The common characteristic of chronic infections, such as human immunodeficiency virus [4], hepatitis C virus (HCV) or hepatitis B virus (HBV) is that anti-virus CTLs are initially stimulated, but later become quantitatively and qualitatively defective leading to a stepwise progression of functional exhaustion and incapability of clearing pathogens [3]. These exhausted CTLs express some immune inhibitory molecules, such as programmed death-1 (PD-1), T-cell Ig and mucin protein-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) [3] [5] [6]. It has been found that longer duration of the chronic infection or severe loss of CD4+ T cell help often leads to more serious CTL exhaustion [1] [13], and the final stage of CTL exhaustion often results in depletion of virus-specific CTLs [8] [10]
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