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.
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.