T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance - PubMed (original) (raw)

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

B Ye et al. Cell Death Dis. 2015.

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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Figures

Figure 1

Figure 1

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.

Figure 2

Figure 2

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 (↓↓)

Figure 3

Figure 3

Immunotherapy for HBV treatment achieved by restoration of exhausted T cells. Exhausted T cells are subject to a number of signaling pathways through which inhibitory receptors can transmit suppressive signals to inhibit functional and proliferative responses during chronic HBV infection. Existing data support that inhibitory receptors including PD-1, CTLA-4, TIM-3 and CD244 all take part in the immunoregulatory mechanism of T-cell exhaustion. Therefore, the restoration of exhausted T-cell function appears effective by either blocking one of these inhibitory receptors or simultaneously blocking several inhibitory molecules. Besides, blocking inhibitory cytokines such as IL-10 or TGF-β are also considered to be a beneficial approach to modulate the function of T cells. After antibody blockade, the ability of T cells to proliferate and secrete cytokines can be restored in chronic HBV-infected patients. Based on these observations, immunotherapeutic approaches deserve better exploration for anti-viral treatment of HBV patients

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