Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Yong, Yean Kong; Saeidi, Alireza; Tan, Hui; Rosmawati, Mohamed; Enström, Philip F; Batran, Rami Al; Vasuki, V; Chattopadhyay, Indranil; Murugesan, Amudhan; Vignesh, Ramachandran; Kamarulzaman, Adeeba; Jayakumar, R.; Ansari, Abdul Wahid; Vadivelu, Jamuna; Ussher, James E.; Vijayakumar, V.; Larsson, Marie; Shankar, Esaki Muthu

doi:10.3389/fimmu.2018.00472

Cited by 80 publications

(91 citation statements)

References 60 publications

(60 reference statements)

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“…Moreover, the abundance of this metacluster was reduced even further in cirrhotic compared to non-cirrhotic PBC patients. This finding is consistent with studies of other chronic liver diseases, including hepatitis B viral infection 26 and hepatocellular carcinoma 27 , which implicate exhaustion and loss of MAIT cells with worsening liver damage. Considering the apparent importance of these cells in PBC, our future efforts should include additional MAIT-specific markers such as the MAITinvariant T cell receptor (Vα7.2).…”

Section: Discussionsupporting

confidence: 91%

Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis

Jang

Juran

Cunningham

et al. 2020

Preprint

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The relationship between Primary Biliary Cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n=33) and age-/sex-matched healthy controls (n=33) to obtain immune cell abundance and marker expression profiles. Hiearchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3 + TCRgd + ), CD8 + T cells (CD3 + CD8 + CD161 + PD1 + ), and memory B cells (CD3 -CD19 + CD20 + CD24 + CD27 + ) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3 -CD19 + CD20 + CD24 -CD27 -) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of CD8 + CD161 + T cells and memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients.Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies.

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Section: Discussionsupporting

confidence: 91%

Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis

Jang

Juran

Cunningham

et al. 2020

Preprint

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“…Hepatitis B virus (HBV) infection is a major cause of HCC [10], and NKp30-B7-H6 interaction could aggravate hepatocyte damage through the upregulation of interleukin-32 in HBV-related acute-on-chronic liver failure [11]. However, to date, the exact role of B7-H6 expression in the oncogenesis and progression of HCC remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Expression of B7-H6 expression in human hepatocellular carcinoma and its clinical significance

Chen

Feng

et al. 2018

Cancer Cell Int

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BackgroundRecent studies have suggested that B7-H6, a new member of the B7 family of ligands, not only is a crucial regulator of NK cell-mediated immune responses but also has important clinical implications due to its abnormal expression in many human cancers. We have previously reported that higher B7-H6 expression levels in ovarian cancer tissues are positively correlated with tumor metastasis and cancer progression. To date, the expression of B7-H6 in human hepatocellular carcinoma (HCC) and the clinical significance of B7-H6 expression still remain elusive.MethodsIn the present study, the expression level of B7-H6 was examined in both HCC tissues and HCC cell lines (HepG2 and SMMC-7721). And the clinical significance of B7-H6 was analyzed as well.ResultsOur results revealed that B7-H6 was expressed abnormally in HCC tissues, which was greatly related to tumor size. The TCGA data also showed that the B7-H6 mRNA expression level was significantly negatively correlated with the survival of HCC patients. Next, to investigate the functions of B7-H6 in HCC, we successfully constructed B7-H6 knockdown expression human HCC cell lines using the RNA interference technology. Our studies showed that reduced expression of B7-H6 in HepG2 and SMMC-7721 cells significantly attenuated cell proliferation as well as cell migration and invasion. Besides, depletion of B7-H6 greatly induced cell cycle arrest at G1 phase. And also B7-H6 knockdown in HCC cell lines dramatically decreased the C-myc, C-fos and Cyclin-D1 expression.ConclusionsOur present findings suggested that B7-H6 played an important role in oncogenesis of HCC on cellular level, and B7-H6 could be employed to develop immunotherapeutic approaches targeting this malignancy.

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“…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]. Recent studies show that PD-1/PD-L1 pathway contributes to the suppression of HBV-specific T cell function in both HBV transgenic mice and CHB patient [4, 37-40]. In addition, treatment with anti-PD-1 or anti-PD-L1 mAbs results in the enhancement or restoration of antiviral T cell function in mice [37, 38, 41-43].…”

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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Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Cited by 80 publications

References 60 publications

Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis

Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis

Expression of B7-H6 expression in human hepatocellular carcinoma and its clinical significance

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

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