Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells

Dias, Joana; Hengst, Julia; Parrot, Tiphaine; Leeansyah, Edwin; Lunemann, Sebastian; Malone, David F. G.; Hardtke, Svenja; Strauß, Otto; Zimmer, C.; Berglin, Lena; Schirdewahn, Thomas; Ciesek, Sandra; Marquardt, Nicole; Hahn, Thomas von; Manns, Michael P.; Cornberg, Markus; Ljunggren, Hans‐Gustaf; Wedemeyer, Heiner; Sandberg, Johan K.; Björkström, Niklas K.

doi:10.1016/j.jhep.2019.04.009

Cited by 70 publications

(89 citation statements)

References 52 publications

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“…HDV infection causes the most severe form of viral hepatitis; patients with HDV present with high levels of ALT, aspartate aminotransferase (AST) and gamma-glutamyltransferase, and low prothrombin levels, all of which are indicative of liver damage. 12,27,28 The mechanisms involved in the pathogenesis of the disease remain unresolved. 2,28 HDV, similar to HBV and HCV, is a non-cytopathic virus and the viruses share pathogenic similarities, characterized by chronic inflammation, hepatocyte injury and progressive fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…As observed in patients, in this mouse model a significant inflammatory infiltrate is detected in the liver. 12,29 The phenotypic characterization of the hepatic immune infiltrate in AAV-HBV/HDV-coinfected C57BL/6 WT mice revealed a composition of activated CD4 + and CD8 + T cells, proinflammatory macrophages, and NK cells. For a number of viral infections, the activation of a specific T cell response is crucial for the elimination of the virus as well as for the induction of tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 It is known that in patients with HDV the frequency of CD4 + T cells and natural killer (NK) cells in peripheral blood is increased compared to in patients with HBV or HCV, while the frequency of mucosal-associated invariant T (MAIT) cells is decreased. [10][11][12] Interestingly, circulating NK cells have an immunoregulatory rather than cytolytic phenotype, and MAIT cells are functionally impaired. 11,12 Very recently, work by Kefalakes et al 13 and Karimzadeh et al 14 showed a weak but positive correlation between the ex vivo frequency of activated HDVspecific CD8+T cells and liver inflammation, suggesting that cellular responses against the virus might indeed be involved in HDV-mediated liver damage.…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] Interestingly, circulating NK cells have an immunoregulatory rather than cytolytic phenotype, and MAIT cells are functionally impaired. 11,12 Very recently, work by Kefalakes et al 13 and Karimzadeh et al 14 showed a weak but positive correlation between the ex vivo frequency of activated HDVspecific CD8+T cells and liver inflammation, suggesting that cellular responses against the virus might indeed be involved in HDV-mediated liver damage. 13,14 However, there are a number of clinical studies showing that HDV-specific T cell response is very weak or undetectable [15][16][17][18] and that there is no correlation between the magnitude of the T cell response and clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

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TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

et al. 2020

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Background & Aims: HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected. Methods: HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage. Results: AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-a pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-a antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell-and TNF-a-independent. Conclusions: Both host (TNF-a) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-a may offer an attractive strategy to aid control of HDV-induced acute liver damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

et al. 2020

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“…The presence of Tregs in tumor is usually associated with a worse prognosis (85) since this cell type suppress the immune response by inhibiting CD8+ T cell effector functions like degranulation, and production of perforin and granzymes (86). Recent studies are also highlighting the importance of a mucosal-associated invariant T cell population (MAIT) that is able to activate and express cytokines (87) and other effector molecules (88), MAIT cells seem also to be negatively affected by chronic viral hepatitis infection (89).…”

Section: Immune Cellsmentioning

confidence: 99%

Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation

Sällberg

Pasetto

2020

Front. Immunol.

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Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.

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Human liver‐derived MAIT cells differ from blood MAIT cells in their metabolism and response to TCR‐independent activation

et al. 2021

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Mucosal associated invariant T (MAIT) cells are anti‐microbial innate‐like T cells that are abundant in blood and liver. MAIT cells express a semi‐invariant T‐cell receptor (TCR) that recognizes a pyrimidine ligand, derived from microbial riboflavin synthesis, bound to MR1. Both blood and liver derived (ld)‐MAIT cells can be robustly stimulated via TCR or by cytokines produced during bacterial or viral infection. In this study, we compared the functional and transcriptomic response of human blood and ld‐MAIT cells to TCR signals (Escherichia coli or the pyrimidine ligand) and cytokines (IL‐12 + IL‐18). While the response of blood and ld‐MAIT cells to TCR signals were comparable, following cytokine stimulation ld‐MAIT cells were more polyfunctional than blood MAIT cells. Transcriptomic analysis demonstrated different effector programmes of ld‐MAIT cells with the two modes of activation, including the enrichment of a tissue repair signature in TCR‐stimulated MAIT cells. Interestingly, we observed enhancement of IL‐12 signaling and fatty acid metabolism in untreated ld‐MAIT cells compared with blood MAIT cells. Additionally, MAIT cells from blood and liver were modulated similarly by TCR and cytokine signals. Therefore, we report that blood and ld‐MAIT cells are fundamentally different but undergo conserved changes following activation via TCR or by cytokines.

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Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells

Cited by 70 publications

References 52 publications

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation

Human liver‐derived MAIT cells differ from blood MAIT cells in their metabolism and response to TCR‐independent activation

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