Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

Hakim, Mohamad S.; Rahmadika, Nofri; Jariah, Rizka Oktarianti Ainun

doi:10.1002/rmv.2094

Cited by 10 publications

(9 citation statements)

References 138 publications

(438 reference statements)

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“…Our study showed upregulation of inhibitory receptor expression on the surface of circulating CD8 + T cells in patients with chronic HBV infection, which was in complete agreement with several reports [ 14 – 17 ]. However, we observed significantly higher expression of PD1 and TIM3 than of CTLA4 or LAG3 on CD8 + T cells, suggesting that PD1 and TIM3 might have a greater contribution to the T cell dysfunction observed during HBV infection.…”

Section: Discussionsupporting

confidence: 93%

“…Prolonged and/or high coexpression of multiple IRs, such as programmed cell death protein 1 (PD1) and T cell immunoglobulin and mucin domain 3 (TIM3), is a key feature of CD8 + and CD4 + T cell exhaustion in humans [ 7 , 13 ]. Several reports have indicated that IR expression is upregulated on HBV-specific CD8 + T cells [ 14 – 17 ]. Previous studies indicated that CXCR5 + Tfc cells exhibited a reduced state of exhaustion, with lower surface expression of IRs than their counterpart CXCR5 − non-Tfc cells during chronic infection [ 12 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers

et al. 2022

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Background Chronic hepatitis B virus (HBV) infection is characterized by the presence of dysfunctional exhausted CD8+ T cells that hamper viral control. We investigated the phenotypic heterogeneity of exhausted CD8+ T cells in HBV carriers. Methods We enrolled 31 HBV carriers and 23 healthy controls (HCs) in our study. Peripheral blood mononuclear cells (PBMCs) were isolated, and flow cytometry was used to determine the phenotypic distribution of CD8+ T cell subsets. Expression of cytokines such as TNF-α and IFN-γ was detected by quantitative reverse transcription–PCR, a fluorescence flow cytometry-based immunomicrobead assay and flow cytometry. Results There were no significant differences in the baseline characteristics between the 31 HBV carriers and the 23 sex- and age-matched HCs. CD8+ T cells exhibited higher levels of inhibitory receptors (TIM3 and PD1) in the HBV carriers than in the HCs (P < 0.05); in particular, Tfc cells (CXCR5+CD25−) expressed higher levels of TIM3 and PD1 than non-Tfc cells in the HBV carriers. In addition, among the subsets of Tc cells, the Tc17 (CXCR5−CD25−CCR6+) subset displayed increased expression of TIM3 and LAG3 in the HBV carriers. Our findings further showed that CD8+ T cells produced lower levels of IFN-γ, TNF-α, and Granzyme B. Paired analysis of the Tfc subset and the Tc subset indicated that higher levels of cytokines (IFN-γ and TNF-α) were produced by the Tfc subset in the HBV carriers. Among the Tc subsets, the Tc17 subset produced lower levels of cytokines. Conclusion The Tfc subset exhibited an enhanced exhausted phenotype but possessed some functional properties during chronic HBV infection, while the Tc subset showed a lower functional level. The identification of these unique subsets may provide a potential immunotherapeutic target in chronic HBV infection.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers

et al. 2022

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“…IFN-γ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay [ 35 ]. However clinical evidence shows that the CD8+ T cells in CHB patients lose their antiviral function and ability to proliferate, which is characterized by T cell exhaustion, suppressed cytokine production and excessive inhibitory signals [ 36 – 38 ]. The co-inhibitory receptor PD-1, expressed on T-cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, macrophages, endothelial cells and hepatocytes; to attenuate T cell activation, effector functions and survival [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

Liu

Qin

et al. 2020

PLoS ONE

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Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.

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“…IFN-γ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay [32]. However clinical evidence shows that the CD8+ T cells in CHB patients lose their antiviral function and ability to proliferate, which is characterized by T cell exhaustion, suppressed cytokine production and excessive inhibitory signals [33-35]. The co-inhibitory receptor PD-1, expressed on T-cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, macrophages, endothelial cells and hepatocytes; to attenuate T cell activation, effector functions and survival [36].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

Liu

Qin

Liu

et al. 2020

Preprint

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24Programmed death ligand 1 (PD-L1) has been recently shown to be a major 25 obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) 26 on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely 27 used to treat hepatitis B virus(HBV)infection, but its antiviral effect vary greatly 28 and the mechanism is not totally clear. We found that IFN-α/γ induced a marked 29 increase of PD-L1 expression in hepatocytes. Signal and activators of transcription 30 ( Stat1) was then identified as a major transcription factor involved in 31 IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the 32 PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell 33 activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in 34 HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an 35 important role in mediating T cell hyporesponsiveness and inactivating 36 liver-infiltrating T cells in the hepatic microenvironment. These data raise further 37 potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic 38 vaccines. 39 40 42 hepatitis B virus (HBV). Ultimate HBV clearance requires the coordination of the 43 potent T cell immune response and effective humoral immunity. However, -3 -44 HBV-specific T cell response, which plays a vital role in HBV clearance, is severely 45 impaired in chronic hepatitis B (CHB) patients, leading to long-term immune 46 tolerance [1, 2]. Several mechanisms may contribute to HBV-specific T cell tolerance 47 and exhaustion, including upregulation of co-inhibitory molecules such as 48 programmed death 1 (PD-1), T-cell immunoglobulin and mucin domain-49 containing molecule 3 (TIM-3), T-cell immunoglobulin and ITIM domain 50 (TIGIT), lymphocyte-activation gene 3 (LAG3), immunosuppressive prostaglandin 51 E2 (PGE2) receptors, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and proapoptotic 52 protein Bcl2-interacting mediator (Bim) on HBV-specific CD8 + T cells, as well as on 53 CD4+ T cells and NK cells. [3-5]. Additionally, regulatory T cells and suppressive 54 cytokines also contribute to virus-specific T cell failure [6]. 55 Among the co-expressed inhibitory receptors on T cells, programmed death 56 ligand 1 (PD-L1) plays a critical role in impaired T cell immune responses. Of note, 57 its ligand PD-L1, a 40 kDa transmembrane protein, is constitutively expressed on 58 liver DCs, Kupffer cells, stellate cells, liver sinusoidal endothelial cells, and 59 hepatocytes. Binding of PD-L1 to PD-1 leads to T cell dysfunction by inhibiting T 60 cell activation, causing T cell exhaustion, anergy, and T cell apoptosis, as well as by 61 inducing Treg differentiation [7-11]. In addition, elevated PD-L1 levels in liver were 62 observed in chronic necroinflammatory liver diseases and autoimmune hepatitis [12, 63 13]. These indicate the immune regulatory function of the liver microenvironment that 64 may lead to T cell tolerance. 65 As an first-line treatment option, ...

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Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

Cited by 10 publications

References 138 publications

Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers

Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

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