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T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance.

Ye B, Liu X, Li X, Kong H, Tian L, Chen Y - Cell Death Dis (2015)

Bottom Line: Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells.As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases.A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8(+) T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.

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The hierarchical development of T-cell exhaustion during persistent viral infection. In chronic viral infection, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function. As antigen or viral load increases, the expression of coinhibitory receptors such as PD-1, TIM-3, CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness. Furthermore, in a hierarchical manner, exhausted T cells lose their proliferative capacity and effector function, including impaired cytokine production such as IL-2, TNF-α and IFN-γ. Ultimately, in the severe stage of exhaustion, virus-specific T cells can be completely deleted, leading to the loss of virus-specific T-cell responses. The cytokine production is indicated by arrows from decrease (↓) to significant decrease (↓↓)
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fig2: The hierarchical development of T-cell exhaustion during persistent viral infection. In chronic viral infection, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function. As antigen or viral load increases, the expression of coinhibitory receptors such as PD-1, TIM-3, CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness. Furthermore, in a hierarchical manner, exhausted T cells lose their proliferative capacity and effector function, including impaired cytokine production such as IL-2, TNF-α and IFN-γ. Ultimately, in the severe stage of exhaustion, virus-specific T cells can be completely deleted, leading to the loss of virus-specific T-cell responses. The cytokine production is indicated by arrows from decrease (↓) to significant decrease (↓↓)

Mentions: In chronic infection of human and mice, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function summarized in Figure 2. As antigen or viral load increases in chronic infection, the expression of coinhibitory receptors such as PD-1, T-cell immunoglobulin domain and mucin domain 3 (TIM-3), CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness.25, 26, 27, 28 The elimination of virus was largely hindered by the reduced number and weak virus-specific T-cell response during persistent infection.29 To comprehend the escape and tolerance mechanism of HBV in chronic hepatitis B (CHB) patients, more and more researchers have begun to explore the appearance and essence of CD8+ T-cell exhaustion in HBV-infected patients. Recently, the related mechanism analyzed by GeneChip technology revealed that an apoptosis gene Bim (Bcl2-interacting mediator) was consistently and significantly expressed in HBV-specific CD8+ T cells from CHB patients compared with those in resolved patients; hence, Bim-mediated apoptosis may contribute to the exhausted state of CD8+ T cells and impede their response to persist viral replication.10


T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance.

Ye B, Liu X, Li X, Kong H, Tian L, Chen Y - Cell Death Dis (2015)

The hierarchical development of T-cell exhaustion during persistent viral infection. In chronic viral infection, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function. As antigen or viral load increases, the expression of coinhibitory receptors such as PD-1, TIM-3, CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness. Furthermore, in a hierarchical manner, exhausted T cells lose their proliferative capacity and effector function, including impaired cytokine production such as IL-2, TNF-α and IFN-γ. Ultimately, in the severe stage of exhaustion, virus-specific T cells can be completely deleted, leading to the loss of virus-specific T-cell responses. The cytokine production is indicated by arrows from decrease (↓) to significant decrease (↓↓)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385920&req=5

fig2: The hierarchical development of T-cell exhaustion during persistent viral infection. In chronic viral infection, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function. As antigen or viral load increases, the expression of coinhibitory receptors such as PD-1, TIM-3, CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness. Furthermore, in a hierarchical manner, exhausted T cells lose their proliferative capacity and effector function, including impaired cytokine production such as IL-2, TNF-α and IFN-γ. Ultimately, in the severe stage of exhaustion, virus-specific T cells can be completely deleted, leading to the loss of virus-specific T-cell responses. The cytokine production is indicated by arrows from decrease (↓) to significant decrease (↓↓)
Mentions: In chronic infection of human and mice, T-cell exhaustion is a well-defined state characterized by stepwise and progressive loss of T-cell function summarized in Figure 2. As antigen or viral load increases in chronic infection, the expression of coinhibitory receptors such as PD-1, T-cell immunoglobulin domain and mucin domain 3 (TIM-3), CTLA-4 and CD244 (2B4) were remarkably increased on the surface of exhausted T cells, which is closely associated with their unresponsiveness.25, 26, 27, 28 The elimination of virus was largely hindered by the reduced number and weak virus-specific T-cell response during persistent infection.29 To comprehend the escape and tolerance mechanism of HBV in chronic hepatitis B (CHB) patients, more and more researchers have begun to explore the appearance and essence of CD8+ T-cell exhaustion in HBV-infected patients. Recently, the related mechanism analyzed by GeneChip technology revealed that an apoptosis gene Bim (Bcl2-interacting mediator) was consistently and significantly expressed in HBV-specific CD8+ T cells from CHB patients compared with those in resolved patients; hence, Bim-mediated apoptosis may contribute to the exhausted state of CD8+ T cells and impede their response to persist viral replication.10

Bottom Line: Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells.As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases.A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8(+) T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.

Show MeSH
Related in: MedlinePlus