Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection

Schurich, Anna; Khanna, Pooja; Lopes, Andre; Han, Ki Jun; Peppa, Dimitra; Micco, L.; Nebbia, Gaia; Kennedy, Patrick T.; Geretti, Anna María; Dusheiko, Geoffrey; Maini, Mala K.

doi:10.1002/hep.24249

Cited by 275 publications

(248 citation statements)

References 26 publications

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“…14,44 Persistent HBV infection impairs HBV-specific CD8 1 T-cell function and results in the exhausted-phenotype CD8 1 cells that fail to clear virus. 45,46 In our study, our results demonstrate that blockage of TNF-a leads to increasing liver-infiltrating PD-1 high CD127 low -exhausted phenotype CD8 1 T cells in mice with HBV persistence. These results indicate that in HBV persistence, blockage of TNF-a will further impair the adaptive immune response and that TNF-a is crucial for maintaining an effective anti-HBV immune response.…”

Section: Discussionsupporting

confidence: 56%

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose-and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1 high CD127 low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-a-blocking agents.

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Section: Discussionsupporting

confidence: 56%

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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“…The local concentration of IFN-c-producing HBV-specific CD8 1 T cells in liver has been demonstrated as being key to the func- tional restoration of anti-HBV-specific immunity in persistent HBV infection. 54,55 IFN-c also promotes a non-cytopathic mechanism of HBV elimination that can limit liver damage during the immune-clearance of HBV. 56 Consistent with this, we observed infiltration of IFN-c-producing CD8 1 T cells in the livers of HBsAg-Tg mice in the 33GM-CSF1rHBVvac treated group (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

Wang

Dong²,

Xiao

et al. 2015

Cell Mol Immunol

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic (HBsAg-Tg) animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-c production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8 1 T cells from immunized animals, antigen-specific CD8 1 T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients. Cellular & Molecular Immunology

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“…Several molecular mechanisms have been reported for the involvement of T cell tolerance and exhaustion, most likely driven by long-term intensive viral antigenic stimulation in CHB, which includes both direct and indirect mechanisms that may act synergistically. The direct effects caused by intrinsic defects include upregulation of coinhibitory molecule programmed death-1 on T cells and its ligand programmed death-L1 on dendritic cells (DCs) (6,7), as well as CTLA-4 and proapoptotic protein Bcl2-interacting mediator on HBV-specific CD8 + T cells (8,9). The indirect effects caused by extrinsic defects include enhanced regulatory T cell (Treg) activities and the tolerogenic nature of the liver microenvironment (2,10).…”

mentioning

confidence: 99%

“…The indirect effects caused by extrinsic defects include enhanced regulatory T cell (Treg) activities and the tolerogenic nature of the liver microenvironment (2,10). Further understanding the molecular defects underlying T cell hyporesponsiveness will allow the development of new strategies for the establishment of immunotherapeutic regimens by targeted reversal of tolerizing mechanisms (2,(7)(8)(9).…”

mentioning

confidence: 99%

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

Wang

Zhang

et al. 2013

The Journal of Immunology

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More than 350 million people are chronically infected with hepatitis B virus, and dysfunctional T cell responses contribute to persistent viral infection and immunopathogenesis in chronic hepatitis B (CHB). However, the underlying mechanisms of T cell hyporesponsiveness remain largely undefined. Given the important role of microRNA-146a (miR-146a) in diverse aspects of lymphocyte function, we investigated the potential role and mechanism of miR-146a in regulating T cell immune responses in CHB. We found that miR-146a expression in T cells is significantly upregulated in CHB compared with healthy controls, and miR-146a levels were correlated with serum alanine aminotransaminase levels. Both inflammatory cytokines and viral factors led to miR-146a upregulation in T cells. Stat1 was identified as a miR-146a target that is involved in antiviral cytokine production and the cytotoxicity of CD4+ and CD8+ T cells. In vitro blockage of miR-146a in T cells in CHB greatly enhanced virus-specific T cell activity. Therefore, our work demonstrates that miR-146a upregulation in CHB causes impaired T cell function, which may contribute to immune defects and immunopathogenesis during chronic viral infection.

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Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection

Cited by 275 publications

References 26 publications

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

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