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J Hepatol. 2019 Aug;71(2):301-312. doi: 10.1016/j.jhep.2019.04.009. Epub 2019 May 14.

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

Author information

1
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
2
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
3
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore 169587, Singapore.
4
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
5
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
6
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
7
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
8
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: niklas.bjorkstrom@ki.se.

Abstract

BACKGROUND & AIMS:

Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells highly enriched in the human liver, has not been extensively studied in clinical HDV infection.

METHODS:

MAIT cells from a sizeable cohort of patients with chronic HDV were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from hepatitis B virus (HBV) monoinfected patients and healthy controls.

RESULTS:

Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV monoinfection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38hiPD-1hiCD28loCD127loPLZFloEomesloHelioslo cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of proinflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection.

CONCLUSIONS:

These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss of MAIT cells as the HDV-associated liver disease progresses.

LAY SUMMARY:

Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. We found that in patients with HDV, a subset of innate-like T cells called mucosa-associated invariant T cells (or MAIT cells), which are normally abundant in peripheral blood and the liver, are activated, functionally impaired and severely depleted.

KEYWORDS:

Hepatitis B; Hepatitis D; Immunology; T lymphocytes

PMID:
31100314
PMCID:
PMC6642010
[Available on 2020-08-01]
DOI:
10.1016/j.jhep.2019.04.009

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