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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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Related in: MedlinePlus

Mechanisms contributing to the exhaustion of HBV-specific CD8+ T cells. There are several mechanisms involved in T-cell exhaustion during chronic HBV infection, including high viral (or antigen) load, loss of CD4+ T-cell help, suppressive cytokines IL-10 and TGF-β and DCs, as well as Treg cells, which are the major sources of the immunosuppressive cytokines IL-10 and TGF-β. All of these factors were able to promote the exhaustion of T cells during chronic HBV infections.
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fig1: Mechanisms contributing to the exhaustion of HBV-specific CD8+ T cells. There are several mechanisms involved in T-cell exhaustion during chronic HBV infection, including high viral (or antigen) load, loss of CD4+ T-cell help, suppressive cytokines IL-10 and TGF-β and DCs, as well as Treg cells, which are the major sources of the immunosuppressive cytokines IL-10 and TGF-β. All of these factors were able to promote the exhaustion of T cells during chronic HBV infections.

Mentions: In recent years, investigations of the mechanisms underlying these impaired T cells in patients who develop chronic HBV infection have been on the increase. It has been established that several mechanisms may contribute to the dysfunction of HBV-specific T cells, such as continuously high viral load and high antigen levels, suppressive cytokines including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), dendritic cells (DCs) and regulatory T (Treg) cells, which were able to result in a progressive loss of T-cell function and cause HBV-specific T cells to become exhausted7, 8 (Figure 1). Such ‘exhausted T cells' have been correlated with a hierarchical dysfunction of their proliferative capacity, effector function (impaired cytokine production) and increased apoptosis.9, 10, 11 Emerging evidences have indicated that during chronic infection, exhausted T cells develop not only with the change of phenotype but also with the distinction of function; finally, these dysfunctional T cells progress to apoptosis because of the defect of differentiating into memory T cells.12 Functional exhaustion of T cells was not only observed in chronic HBV infection but also has been confirmed in cancers owing to the ability of developing high antigen and immunosuppressive environment. In cancer environment, tumor-reactive T cells have also shown an upregulation of inhibitory molecules, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which resemble T-cell exhaustion in chronic viral infection.13, 14 Specifically, studies on human metastatic melanoma have shown that both CD8+ and CD4+ tumor-infiltrating lymphocytes had significantly higher expression of PD-1 and CTLA-4, whereas PD-1 blockade enhanced the frequency of cytokine-producing cells.15, 16 Furthermore, another clinical study stated that blocking the PD-1 immune checkpoint in patients with treatment-refractory solid tumors was well tolerated and associated with the evidence of antitumor activity.17 For other virus-infected diseases such as LCMV (lymphocytic choriomeningitis), HCV (hepatitis C virus) and HIV (human immunodeficiency virus) in mice and humans, there were numerous evidences supporting that restoring the function of intrahepatic T-cell function can be achieved by blocking single or a combination of inhibitory pathways.18, 19, 20, 21, 22 Recent efforts have proposed that specific transcription factors such as T-bet were associated with T-cell exhaustion, which were supported by the evidence that T-bet directly repressed transcription of the gene encoding PD-1, and high T-bet expression sustained exhausted CD8+ T cells in mice infected with LCMV,23 reminiscent of its role in sustaining exhausted CD4+ T cells.24 Based on the above researches, more and more attention have been focused on the mechanism and clinical significance of T-cell exhaustion in HBV infection. In this paper, we will draw upon the most up-to-date available data to understand the behavior of T cell exhaustion during chronic HBV infection in humans, and meanwhile, we will characterize several potential immunotherapeutics upon the manipulation of inhibitory molecules for the future treatment of chronic HBV infection.


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)

Mechanisms contributing to the exhaustion of HBV-specific CD8+ T cells. There are several mechanisms involved in T-cell exhaustion during chronic HBV infection, including high viral (or antigen) load, loss of CD4+ T-cell help, suppressive cytokines IL-10 and TGF-β and DCs, as well as Treg cells, which are the major sources of the immunosuppressive cytokines IL-10 and TGF-β. All of these factors were able to promote the exhaustion of T cells during chronic HBV infections.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Mechanisms contributing to the exhaustion of HBV-specific CD8+ T cells. There are several mechanisms involved in T-cell exhaustion during chronic HBV infection, including high viral (or antigen) load, loss of CD4+ T-cell help, suppressive cytokines IL-10 and TGF-β and DCs, as well as Treg cells, which are the major sources of the immunosuppressive cytokines IL-10 and TGF-β. All of these factors were able to promote the exhaustion of T cells during chronic HBV infections.
Mentions: In recent years, investigations of the mechanisms underlying these impaired T cells in patients who develop chronic HBV infection have been on the increase. It has been established that several mechanisms may contribute to the dysfunction of HBV-specific T cells, such as continuously high viral load and high antigen levels, suppressive cytokines including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), dendritic cells (DCs) and regulatory T (Treg) cells, which were able to result in a progressive loss of T-cell function and cause HBV-specific T cells to become exhausted7, 8 (Figure 1). Such ‘exhausted T cells' have been correlated with a hierarchical dysfunction of their proliferative capacity, effector function (impaired cytokine production) and increased apoptosis.9, 10, 11 Emerging evidences have indicated that during chronic infection, exhausted T cells develop not only with the change of phenotype but also with the distinction of function; finally, these dysfunctional T cells progress to apoptosis because of the defect of differentiating into memory T cells.12 Functional exhaustion of T cells was not only observed in chronic HBV infection but also has been confirmed in cancers owing to the ability of developing high antigen and immunosuppressive environment. In cancer environment, tumor-reactive T cells have also shown an upregulation of inhibitory molecules, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which resemble T-cell exhaustion in chronic viral infection.13, 14 Specifically, studies on human metastatic melanoma have shown that both CD8+ and CD4+ tumor-infiltrating lymphocytes had significantly higher expression of PD-1 and CTLA-4, whereas PD-1 blockade enhanced the frequency of cytokine-producing cells.15, 16 Furthermore, another clinical study stated that blocking the PD-1 immune checkpoint in patients with treatment-refractory solid tumors was well tolerated and associated with the evidence of antitumor activity.17 For other virus-infected diseases such as LCMV (lymphocytic choriomeningitis), HCV (hepatitis C virus) and HIV (human immunodeficiency virus) in mice and humans, there were numerous evidences supporting that restoring the function of intrahepatic T-cell function can be achieved by blocking single or a combination of inhibitory pathways.18, 19, 20, 21, 22 Recent efforts have proposed that specific transcription factors such as T-bet were associated with T-cell exhaustion, which were supported by the evidence that T-bet directly repressed transcription of the gene encoding PD-1, and high T-bet expression sustained exhausted CD8+ T cells in mice infected with LCMV,23 reminiscent of its role in sustaining exhausted CD4+ T cells.24 Based on the above researches, more and more attention have been focused on the mechanism and clinical significance of T-cell exhaustion in HBV infection. In this paper, we will draw upon the most up-to-date available data to understand the behavior of T cell exhaustion during chronic HBV infection in humans, and meanwhile, we will characterize several potential immunotherapeutics upon the manipulation of inhibitory molecules for the future treatment of chronic HBV infection.

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