Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection

Lopes, Andre; Kellam, Paul; Das, Abhishek; Dunn, Claire; Kwan, Antonia; Turner, J.; Peppa, Dimitra; Gilson, Richard; Gehring, Adam J.; Bertoletti, Antonio; Maini, Mala K.

doi:10.1172/jci33402

Cited by 195 publications

(155 citation statements)

References 48 publications

(62 reference statements)

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“…This hypothesis of TCR-mediated bim regulation is further supported by a recent study with HBV-specific CD8 1 T cells from patients with chronic HBV infection [40]. Here, bim levels were up-regulated in HBV-specific CTL contributing to their inability to survive and control viral replication [40].…”

Section: Discussionsupporting

confidence: 52%

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Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

et al. 2010

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To develop cytolytic effector functions, CD8 1 T lymphocytes need to recognize specific Ag/ MHC class I complexes in the context of costimuli on Ag-presenting DC. Thereafter they differentiate into effector and memory CTL able to confer protection against pathogen infection. Using transgenic mice with DC-selective MHC class I expression and DC-specific versus ubiquitous vaccination regimen, we found that DC are sufficient to prime CTL responses. However, Ag recognition on parenchymal non-professional APC negatively affected CD8 1 T-cell responses in mice by inducing expression of the pro-apoptotic bcl2-family member bim in CTL. This unexpected induction of apoptosis in the early phase of effector CTL accumulation lead to suboptimal clonal burst size and diminished long-term memory. Thus, our data demonstrate that effector CTL differentiation and apoptosis are regulated independently. Moreover, Ag distribution on cells other than DC critically reduces CTL responses.

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Section: Discussionsupporting

confidence: 52%

“…Here, bim levels were up-regulated in HBV-specific CTL contributing to their inability to survive and control viral replication [40]. Death of CTL was induced by Ag recognition via TCR, as in chronically infected individuals excess amounts of HBV-Ag are produced [40].…”

Section: Discussionmentioning

confidence: 99%

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

et al. 2010

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“…55,56 Consistently, Bim was upregulated on HBV-specific CD8 1 T cells during chronic HBV infection and contributed to the deletion of HBV-specific CD8 1 T cells. 57 LSECs are unique liver-resident antigen-presenting cells that are capable of antigen cross-presentation and induction of CD8 1 T-cell tolerance under noninflammatory conditions 58 or promotion of CD8 1 T-cell immunity under certain conditions, such as viral infection. 59 Recently, we examined functional maturation of LSECs by TLR ligand stimulation, demonstrating that pretreatment of LSECs with P3C (TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce specific T-cell immunity.…”

Section: Activation Of Tlr-mediated Signaling Pathways Modulates Hbv-mentioning

confidence: 99%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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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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Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection

Cited by 195 publications

References 48 publications

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

Parenchymal cells critically curtail cytotoxic T‐cell responses by inducing Bim‐mediated apoptosis

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

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

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