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 VirusImmunology, 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 CD38^hiPD-1^hiCD28^loCD127^loPLZF^loEomes^loHelios^lo 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.