CD8+CD28− T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection

2019 ◽  
Vol 133 (17) ◽  
pp. 1917-1934
Author(s):  
Madhuparna Nandi ◽  
Sourina Pal ◽  
Sumantra Ghosh ◽  
Bidhan Chandra Chakraborty ◽  
Debangana Dey ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Hepatitis B E Antigen ◽  
Tnf Α ◽  
Ifn Γ

Abstract During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28− T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28− T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28− T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28− T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28− T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28− T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28− T-cell killing. Both CD28+ and CD28− T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28− T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28− T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28− T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28− T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.

Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic Hepatitis B patients

2011 ◽  
Vol 139 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Fen Liu ◽  
Fuyi Tong ◽  
Yan He ◽  
Haiyan Liu
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Peripheral Blood ◽  
Cd4 T Cells

scholarly journals Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

2019 ◽  
Author(s):  
Yurong Gu ◽  
Yifan Lian ◽  
Qiaolan Zheng ◽  
Zexuan Huang ◽  
Lin Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Natural Killer ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Nkt Cells ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.

IL-35 inhibits HBV antigen-specific IFN-γ-producing CTLs in vitro

2015 ◽  
Vol 129 (5) ◽  
pp. 395-404 ◽  
Author(s):  
Xuefen Li ◽  
Li Tian ◽  
Yuejiao Dong ◽  
Qiaoyun Zhu ◽  
Yiyin Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cellular Immune Response ◽  
Cd4 T Cells ◽  
Ifn Γ ◽  
Cellular Immune

Inhibitory cytokine, interleukin-35 (IL-35), is highly expressed in CD4+ T-cells from CHB patients and plays an important role in the inhibition of the cellular immune response, which contribute to the development and progression of chronic hepatitis B.

scholarly journals Complementarity-Determining Region 3 Size Spectratypes of T Cell Receptor β Chains in CD8+T Cells following Antiviral Treatment of Chronic Hepatitis B

2010 ◽  
Vol 55 (2) ◽  
pp. 888-894 ◽  
Author(s):  
Shi-Wu Ma ◽  
Yong-Yin Li ◽  
Guang-Wen Zhang ◽  
Xuan Huang ◽  
Jian Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Antiviral Therapy ◽  
Chronic Hepatitis B ◽  
T Cell Receptor ◽  
Virological Response ◽  
Peripheral Blood ◽  
Cell Receptor

ABSTRACTAn increased CD8+T cell response to hepatitis B virus (HBV) peptides occurs between 12 and 24 weeks after starting antiviral therapy for chronic hepatitis B. It is not known whether these cells have antiviral function. The aim of this study was to determine whether clonal expansions of CD8+T cells at these time points predict the virological response to therapy. Peripheral blood CD8+T cells were obtained from 20 patients treated with lamivudine or telbivudine for chronic hepatitis B at baseline, 12 weeks, and 24 weeks. The CDR3 spectratype of each T cell receptor (TCR) β chain variable region (Vβ) gene family was analyzed, and the changes in the numbers of Vβ families with clonal expansions were compared in subjects with (n= 12) and without (n= 8) a virological response (52 week HBV DNA < 300 copies/ml). The number of CD8+TCR Vβ families with clonal expansions at 12 weeks relative to baseline (median [10th to 90th percentile], +2.5 [0 to +7] versus +1 [0 to +2],P= 0.03) and at 24 weeks relative to 12 weeks (+1 [0 to +2] versus −1 [−3 to +4],P= 0.006) was higher in subjects with a virological response versus subjects without a virological response, as were interleukin-2 (IL-2) but not IL-21 mRNA levels in peripheral blood mononuclear cells. The duration of new expansions at 12 weeks was higher (P< 0.0001) in responders. Increased numbers of CD8+T cell expansions after antiviral therapy are associated with a virological response to treatment. These CD8+T cells are a potential target for a therapeutic vaccine for chronic hepatitis B.

scholarly journals Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

2019 ◽  
Author(s):  
Yurong Gu ◽  
Yifan Lian ◽  
Qiaolan Zheng ◽  
Zexuan Huang ◽  
Lin Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Natural Killer ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Nkt Cells ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.

scholarly journals Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

2020 ◽  
Author(s):  
Yurong Gu ◽  
Yifan Lian ◽  
Qiaolan Zheng ◽  
Zexuan Huang ◽  
Lin Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Natural Killer ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Nkt Cells ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background: Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods: We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results: levels of IFN-γ + and TNF-α + CD4 + and CD8 + T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ + , TNF-α + and IL-2 + CD4 + and CD8 + T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ + NKT cells were associated with HBV DNA, while IFN-γ + CD4 + and CD8 + T cells were correlated with age. Conclusion : HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.

scholarly journals Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2563
Author(s):  
Valeria Barili ◽  
Andrea Vecchi ◽  
Marzia Rossi ◽  
Ilaria Montali ◽  
Camilla Tiezzi ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Stress Responses ◽  
T Cell Exhaustion ◽  
Virus Infections ◽  
Cell Exhaustion

In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.

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