scholarly journals Pathogenic CD8 T cells defined by longitudinal liver sampling in chronic hepatitis B patients starting antiviral therapy

2021 ◽  
Author(s):  
Shirin Nkongolo ◽  
Deeqa Mahamed ◽  
Adrian Kuipery ◽  
Juan D. Sanchez Vasquez ◽  
Samuel C. Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Antiviral Therapy ◽  
Chronic Hepatitis B ◽  
Liver Damage ◽  
Cd8 T Cells ◽  
Human Liver ◽  
Cd8 T Cell

Accumulation of activated immune cells results in non-specific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. We enrolled 15 CHB patients with active liver damage to receive antiviral therapy, and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8 T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8 T cells, resulting in non-specific Fas ligand-mediated killing of target cells. These results define a CD8 T cell population in the human liver that can drive pathogenesis, and a key pathway involved in their function in CHB patients.

scholarly journals Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

2008 ◽  
Vol 205 (9) ◽  
pp. 2111-2124 ◽  
Author(s):  
Abhishek Das ◽  
Matthew Hoare ◽  
Nathan Davies ◽  
A. Ross Lopes ◽  
Claire Dunn ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Chronic Hepatitis B Virus ◽  
B Virus

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.

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.

scholarly journals HBV-Specific CD8+ T-Cell Tolerance in the Liver

2021 ◽  
Vol 12 ◽  
Author(s):  
Ian Baudi ◽  
Keigo Kawashima ◽  
Masanori Isogawa
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Dysfunction ◽  
Cell Responses ◽  
T Cell Dysfunction

Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.

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.

Immune profile of peripheral blood T-lymphocyte subpopulations in chronic hepatitis B

2021 ◽  
Vol 30 (3) ◽  
pp. 173-178
Author(s):  
Hanan E. Alrashidi ◽  
Safaa M. EL-Ageery ◽  
Iman M. Fawzy ◽  
Mona M Arafa ◽  
Raghda E. Farag ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Elevated Level ◽  
Lymphocyte Subpopulations ◽  
T Lymphocyte Subpopulations

Background: The role of immune response to chronic hepatitis B virus (HBV) infection is complex; and the specific T-cell response to this infection can determine the duration and the extent of liver disease. Objective: This study aimed at assessing the profile of Tlymphocyte subpopulations in chronic hepatitis B (CHB) patients and its association with HBV replication. Methodology: The case group included 50 CHB patients with normal liver function tests (LFTs); and the control group included 50 age and sexmatched healthy individuals. The HBV markers, LFTs and serum viral load were measured in cases. Blood CD4 and CD8 T-lymphocyte subpopulations and the CD4/CD8 ratio were assessed in both groups by flow cytometry. Results: Our results showed significantly higher CD8 T-cells; significantly lower CD3 and CD4 T-cells; markedly reduced CD4/CD8 ratio in the cases as compared to the controls (P<0.001, for all). This T-cell impairment was also significantly linked to HBeAg positivity and elevated level of viraemia. The increased level of CD8 T-cells was significantly linked to both the HBeAg positivity (P<0.001) and the elevated level of viraemia (P=0.005), whereas the decreased levels of CD3, CD4 T-cells and CD4/CD8 ratio were significantly linked to both HBeAg positivity (P<0.001, in all) and the elevated level of viraemia (P<0.001, P=0.001& P=0.007, respectively). Conclusion: T-lymphocyte subpopulations imbalance could be expected by measuring the serum HBVeAg and the viraemia level in CHB patients exhibiting normal LFTs. These parameters are recommended to be measured regularly for the cellular immune function assessment.

scholarly journals Effects of Co-infection With Clonorchiasis Sinensis on T Cell Exhaustion Levels in Patients With Chronic Hepatitis B

2021 ◽  
Author(s):  
Huimin Dong ◽  
Minqi Luo ◽  
Mei Shang ◽  
Yang Wang ◽  
Yuechun Fu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Hbv Dna ◽  
T Cell Exhaustion ◽  
Expression Levels ◽  
Cell Exhaustion

Abstract BackgroundTo investigate the effects of co-infection with C. sinensis on T cell exhaustion levels in patients with chronic hepatitis BMethodsInhibitory receptors and suppressive cytokines expression in circulating CD4+ and CD8+ T cells was detected by flow cytometry. The correlations between PD-1 and TIM-3 expression and alanine aminotransaminase (ALT) levels, aspartate aminotransferase (AST) levels and HBV DNA levels were analyzed using GraphPad Prism 7.0. ResultsPD-1 and TIM-3 expression levels were significantly higher on CD4+T and CD8+T cells from co-infected patients than on those from the HBV patients. In addition, CD4+T cells and CD8+T cells function was inhibited by C. sinensis and HBV coinfection, secreting low levels of IFN-γ, IL-2 and TNF-α. Then, a significant positive correlation was found between the PD-1 and TIM-3 expression levels on T cells and the AST ,ALT levels and HBV DNA levels.ConclusionsOur current results suggested that C. sinensis co-infection could exacerbate T cell exhaustion in patients with chronic hepatitis B. Furthermore, it maybe one possible reason for the weaker response to antiviral therapies and the chronicity of HBV infection in co-infected patients. We must realize that the importance of C.sinensis treatment for HBV infected patients. It might provide useful information for the clinical doctors to choose the right treatment plans.

scholarly journals In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2273
Author(s):  
Katrin Manske ◽  
Annika Schneider ◽  
Chunkyu Ko ◽  
Percy A. Knolle ◽  
Katja Steiger ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Recombinant Adenovirus ◽  
Hbv Infection ◽  
High Dose ◽  
Viral Immunity

Immunity against hepatitis B virus (HBV) infection is complex and not entirely understood so far, including the decisive factors leading to the development of chronic hepatitis B. This lack of a mechanistic understanding of HBV-specific immunity is also caused by a limited number of suitable animal models. Here, we describe the generation of a recombinant adenovirus expressing an HBV 1.3-overlength genome linked to luciferase (Ad-HBV-Luc) allowing for precise analysis of the quantity of infected hepatocytes. This enables sensitive and close-meshed monitoring of HBV-specific CD8 T cells and the onset of anti-viral immunity in mice. A high dose of Ad-HBV-Luc developed into chronic hepatitis B accompanied by dysfunctional CD8 T cells characterized by high expression of PD1 and TOX and low expression of KLRG1 and GzmB. In contrast, a low dose of Ad-HBV-Luc infection resulted in acute hepatitis with CD8 T cell-mediated elimination of HBV-replicating hepatocytes associated with elevated sALT levels and increased numbers of cytotoxic HBV-specific CD8 T cells. Thus, the infectious dose was a critical factor to induce either acute self-limited or chronic HBV infection in mice. Taken together, the new Ad-HBV-Luc vector will allow for highly sensitive and time-resolved analysis of HBV-specific immune responses during acute and chronic infection.

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