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

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 being highly enriched in the human liver, have not been extensively studied in clinical HDV infection.

METHODS: 

MAIT cells from a sizeable cohort of chronic HDV patients were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from HBV mono-infected 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 mono-infection. 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 pro-inflammatory 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 as the HDV-associated liver disease progresses.

LAY SUMMARY: 

MAIT cells, unconventional T cells abundant in peripheral blood and liver, are activated, functionally impaired, and severely depleted from the peripheral blood of HDV-patients.

Authors

Dias J1, Hengst J2, Parrot T1, Leeansyah E3, Lunemann S4, Malone DFG1, Hardtke S5, Strauss O1, Zimmer CL1, Berglin L1, Schirdewahn T5, Ciesek S6, Marquardt N1, von Hahn T5, Manns MP5, Cornberg M5, Ljunggren HG1, Wedemeyer H7, Sandberg JK1, Björkström NK8. J Hepatol. 2019 May 6. pii: S0168-8278(19)30270-3. doi: 10.1016/j.jhep.2019.04.009. [Epub ahead of print]

Author Information

1.  Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

2.  Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

3.  Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 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, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: niklas.bjorkstrom@ki.se.

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