The pivotal role of CD8+ T cells in hepatitis E virus infection.
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ABSTRACT:
SUBMITTER: Bruggemann Y
PROVIDER: S-EPMC9413854 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
The pivotal role of CD8+ T cells in hepatitis E virus infection.
Brüggemann Yannick Y Klöhn Mara M Todt Daniel D
Journal of hepatology 20220814 4
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Project description:Antibodies as well as memory B cells are the potential correlates of a protective immune response against hepatitis E virus (HEV) infection. Literature on the role of B regulatory cells (Bregs) in acute viral infections is limited. We have evaluated the role of IL-10 expressing Bregs in HEV infection. A total of 108 acute hepatitis E patients, 55 hepatitis E recovered individuals and 128 HEV naïve healthy controls were enrolled. The percentages of peripheral CD19+, immature CD19+CD24hiCD38hi, mature CD19+CD24intCD38int and memory CD19+CD24hiCD38- B cells were analyzed by flowcytometry. Intracellular cytokine staining for IL-10 and TGF-β, HEV-rORF2p specific T cell response (IFN-γ expression) pre/post IL-10/IL-10R blocking and CD19+IL-10+ B cells-depletion based assays were carried out to assess the functionality of Bregs. The percentage of HEV-rORF2p specific immature B cell phenotype was significantly higher in acute hepatitis E patients compared to hepatitis E recovered individuals and controls. Significantly higher IL-10 expression on B and HEV-rORF2p stimulated immature B cells of acute hepatitis E patients compared to controls indicated that Bregs are functional and HEV-rORF2p specific. Enhanced IFN-γ expression on CD8+ T cells upon IL-10/IL-10R blocking and also post CD19+IL-10+ B cells depletion suggested that CD3+CD8+IFN-γ + T cells corroborate the regulatory potential of Bregs via IL-10 dependent mechanism. We have identified HEV specific functional, immature CD19+CD24hiCD38hi B cells having IL-10 mediated regulatory activities and a potential to modulate IFN-γ mediated T cell response in Hepatitis E. The prognostic/pathogenic role of Bregs in recovery from severe hepatitis E needs evaluation.
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Project description:The transfer and development of chronic hepatitis B virus (HBV) infection is associated with the T cell immune response, therefore investigating the key regulators of cell immune response is needed to improve chronic HBV treatment. Blood samples from patients with chronic HBV infection were used to confirm the correlation between HBV infection stage and CD160 receptor expression levels in CD8+ T cells, the CD8+ T cells are used to research the mechanism of T cell immune response modulation, moreover, C3H/HeN mice with reduced CD160 expression levels were used to investigate the association between long non-coding (lnc)RNA-CD160 and HBV infection. Long non-coding (lnc)RNA-CD160 and histone-modification enzyme gene histone deacetylase 11 (HDAC11) expression levels were negatively associated with CD160 expression. lncRNA-CD160 can inhibit the secretion of IFN-? and TNF-? through HDAC11 recruitment and bind to HDAC11 to form a complex on the promoters of IFN-? and TNF-?. The HDAC11, IFN-? and TNF-? form a complex and enhance the methylation of H3K9Me1, chromatin changes into the heterochromatin and the transcription of IFN-? and TNF-? is blocked; moreover, the HDAC11/IFN-?/TNF-? complex can also inhibit the secretion of IFN-? and TNF-? in CD160- CD8+ T cells and suppresses the function of CD8+ T cells. Furthermore, small interfering RNA targeting lncRNA-CD160 can block HBV infection progression. lncRNA-CD160 acts as an immune suppressive factor and is expressed at a high level in peripheral blood CD8+ T cells of HBV infected patients. Furthermore, high expression levels of lncRNA-CD160 can contribute to the inhibition of IFN-? and TNF-? secretion in CD8+ T cells and decrease the immune response of CD8+ T cells. Therefore, lncRNA-CD160 may become a new target for immunotherapy of chronic HBV infection in the future and may provide a new therapeutic strategy for the treatment of HBV infection.
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Project description:The molecular mechanisms underlying susceptibility to severe respiratory syncytial virus (RSV) infection remain poorly understood. Herein, we report on the role of osteopontin (OPN) in regulation of RSV infection in human epithelial cells and how interleukin-1 beta (IL-1β), a cytokine secreted soon after RSV infection, when persistently expressed can induce OPN expression leading to increased viral infection. We first compared OPN expression in two human epithelial cell lines: HEK-293 and HEp-2. In contrast to HEp-2, HEK-293 expresses low levels of pro-caspase-1 resulting in decreased IL-1β expression in response to RSV infection. We found a correlation between low IL-1β levels and a delay in induction of OPN expression in RSV-infected HEK-293 cells compared to HEp-2. This phenomenon could partially explain the high susceptibility of HEp-2 cells to RSV infection versus the moderate susceptibility of HEK-293 cells. Also, HEK-293 cells expressing low levels of pro-caspase-1 exhibit decreased IL-1β expression and delayed OPN expression in response to RSV infection. HEK-293 cells incubated with human rIL-1β showed a dose-dependent increase in OPN expression upon RSV infection. Also, incubation with rOPN increased RSV viral load. Moreover, HEp-2 cells or mice infected with a mucogenic RSV strain RSV-L19F showed elevated levels of OPN in contrast to mice infected with the laboratory RSV strain rA2. This correlated with elevated levels of OPN following infection with RSV-L19F compared to rA2. Together, these results demonstrate that increased OPN expression is regulated in part by IL-1β, and the interplay between IL-1β and OPN signaling may play a pivotal role in the spread of RSV infection.
| S-EPMC5909912 | biostudies-literature
Project description:Background & aimsHEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Herein, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans.MethodsRhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV genotype (gt)3 isolate derived from a chronically infected human patient. HEV replication, alanine aminotransferase, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection.ResultsHEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell-depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function.ConclusionsLiver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated rhesus macaques, and a 1-week delay in HEV clearance in CD8+ T cell-depleted rhesus macaques, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection.Lay summaryThe hepatitis E virus (HEV) is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.
| S-EPMC8603813 | biostudies-literature
Project description:Background & aimHepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis.MethodsWe isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8+ T-cell epitopes, and characterized HDV-specific CD8+ T cells. We associated these with HDV sequence variations and clinical features of patients.ResultsWe identified 6 CD8+ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8+ T cells correlated with transaminase activity. CD8+ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8+ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8+ T cells had a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation.ConclusionsCD8+ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8+ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226.
| S-EPMC7367679 | biostudies-literature
Project description:Background & aimsThe hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown.MethodsInnate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage.ResultsThe 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity.ConclusionAntigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.
| S-EPMC10263257 | biostudies-literature
Project description:BackgroundRecent studies reported that the CD4/CD8 T-cell ratio is inversely associated with biomarkers traditionally used to measure immune activation and systemic inflammation in highly active antiretroviral therapy-treated HIV-infected (HIV+) patients. The relation of hepatitis C virus (HCV) coinfection with the CD4/CD8 ratio in HIV+ patients is unknown.MethodsWe examined 50,201 CD4/CD8 ratios measured over 20 years in 3 groups of HIV+ women enrolled in the Women's Interagency HIV Study: HCV antibody negative (n = 1734), cleared HCV (n = 231), and chronic HCV (n = 751) in multivariate models. IFNL4-ΔG genotype and HCV viral load were also considered.ResultsCompared with HCV antibody negative status, chronic HCV infection was associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification (β = -0.08; P = 0.002). Cleared HCV (β = -0.10; P = 0.0009), but not IFNL4-ΔG genotype or HCV viral load, was also associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification.ConclusionsThe association of HCV coinfection with CD4/CD8 ratio is consistent with previously observed associations of HCV coinfection with biomarkers traditionally used to measure immune activation and systemic inflammation in HIV+ patients. These data provide additional support for the use of CD4/CD8 ratio for routine monitoring of immune activation and inflammation in HIV+ patients, including those with HIV/HCV coinfection; however, the unexpected association between cleared HCV and lower CD4/CD8 ratio requires additional study.
| S-EPMC4874499 | biostudies-literature