Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

Kurktschiev, Peter; Raziorrouh, Bijan; Schraut, W.; Backmund, Markus; Wächtler, Martin; Wendtner, Clemens‐Martin; Bengsch, Bertram; Thimme, Robert; Denk, Gerald; Zachoval, Reinhart; Dick, Andrea; Spannagl, Michael; Haas, Jürgen; Diepolder, Helmut M.; Jung, Maria–Christina; Gruener, Norbert H.

doi:10.1084/jem.20131333

Cited by 92 publications

(78 citation statements)

References 47 publications

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“…Similarly, T-bet and Eomes were downregulated in antigen-specific CD8 T cells during chronic HCV-infection [37]. MAIT cells are distinct among T cells in that they express transcription factors for multiple effector programs including PLZF, T-bet, Eomes, and Helios, albeit some, including T-bet at low levels [8].…”

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 96%

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction Mucosal-associated invariant T (MAIT) cells are T cells with innate-like characteristics enriched in human liver and at mucosalCorrespondence: Dr. Niklas K. Björkström e-mail: niklas.bjorkstrom@ki.se sites [1,2]. They express a semi-invariant TCR carrying the Vα7.2 segment together with a restricted Vβ repertoire [1,2]. Upon activation, MAIT cells respond rapidly with cellular cytotoxicity as well as secretion of proinflammatory and anti-viral cytokines such * These authors contributed equally to this work. HCV is an extremely successful pathogen in that it establishes chronic infection in up to 90% of infected humans [9]. The reasons behind the failure of the human immune system to clear HCV are not fully understood but involve viral escape, CD4 and CD8 T-cell exhaustion, as well as NK-cell dysfunction [10][11][12] Until recently, pegylated IFN-α together with ribavirin was used to treat chronic HCV-infection. However, pegylated IFN-α in doses administered to patients has direct inhibitory effects on immune cells [15][16][17][18]. In the last years, treatment of HCV has undergone a revolution with the introduction of highly effective direct-acting antivirals (DAA) that rapidly eliminate the virus [19]. Thus, today the vast majority of patients clear HCV after such IFN-free treatment regimens. This remarkable outcome allows for studies on consequences on immune cell recovery following rapid pathogen removal. In such studies, it was recently shown that both HCVspecific CD8 T cell and NK-cell populations become reinvigorated following viral clearance [20][21][22][23]. However, whether MAIT cells recover upon HCV clearance remains unclear.Here, we performed a comprehensive analysis of MAIT cells in chronic HCV-infection. Specifically, we addressed whether MAIT cell recovery occurs upon HCV-clearance in patients receiving an IFN-free treatment regimen consisting of sofosbuvir and ribavirin. Strikingly, and in contrast to other immune cells, MAIT cells were not reinvigorated following successful HCV-clearance using IFNfree therapy. The results are discussed in relation to the current knowledge on human MAIT cell responses to other viral infections and in the context of immune exhaustion during chronic infections. Results and discussion MAIT cells are among the most severely affected immune cells in chronic HCV-infectionTo determine the impact of chronic HCV-infection on the peripheral blood immune cell compartment, we assessed the major myeloid and lymphoid immune cell subsets in a cohort of HCVpatients and healthy donors by using a 23-parameter flow cytometry staining approach as previously described [24] (Supporting Information Fig. 1). The major phenotype observed in chronic HCV was a severe loss of MAIT cells (Fig. 1A, B). Other immune cell alterations noted were in line with previous studies, including an increase in Tregs [25], a reduced frequency of pDCs [26], and a shift within the CD4...

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Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 96%

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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“…Furthermore, IL-12 treatment combined with PD1 blockade further restores the function of exhausted HBV-specific CD8 + T cells in vitro 131 . A recent study showed that T-bet (also known as TBX21) expression is lacking in dysfunctional CD8 + T cells in chronic HCV infection and HBV infection and that exogenous IL-12 in addition to T-bet induction restores the cytokine production of these CD8 + T cells 132 .…”

Section: Chronic Hepatitis Virus Infectionmentioning

confidence: 99%

Immune responses and immunopathology in acute and chronic viral hepatitis

2016

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Hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for most cases of viral hepatitis. Infection by each type of virus results in a different typical natural disease course and clinical outcome that are determined by virological and immunological factors. HCV tends to establish a chronic persistent infection, whereas HAV does not. HBV is effectively controlled in adults, although it persists for a lifetime after neonatal infection. In this Review, we discuss the similarities and differences in immune responses to and immunopathogenesis of HAV, HBV and HCV infections, which may explain the distinct courses and outcomes of each hepatitis virus infection.

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“…One possibility might be deletion of HBV-specific CD8+ T cells in patients with cHBV as supported by the finding of elevated expression of the proapoptotic molecule Bim 9. Nevertheless, it has been shown that the few detectable HBV-specific CD8+ T cells are functionally impaired, express several inhibitory receptors5 8 10–14 and display a dysregulation of the transcription factor T-bet 7. These findings are indicative of T cell exhaustion in cHBV infection.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

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Alizei

Heim

et al. 2019

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ObjectiveA hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion.DesignBy applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses.ResultsHBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression.ConclusionsOverall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.

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Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction

Abstract: In humans infected with hepatitis B or C, high expression of a protein called T-bet in virus-fighting immune cells is associated with spontaneous clearance of the virus. Absence of T-bet was more often seen in patients whose infections became chronic.

Cited by 92 publications

References 47 publications

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Immune responses and immunopathology in acute and chronic viral hepatitis

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

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