Author information

• ¹Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA.
• ²Laboratory of Cardiac Physiology, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD, USA.
• ³Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA.
• ⁴Laboratory of Pathology, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD, USA.
• ⁵Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA.
• ⁶Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA. Electronic address: Rehermann@nih.gov.

Abstract

Background & aims: The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5-10 years. There is no curative treatment and the mechanisms underlying the accelerated liver disease progression are unknown.

Methods: Innate and adaptive immune responses were studied in blood and liver of 24 HDV-infected patients and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage.

Results: The two main intrahepatic innate immune-cell populations, MAIT cells and NK cells, were reduced in the livers of HDV-infected patients compared to those of uninfected controls but were more frequently activated in the liver compared to the blood. Most intrahepatic CD8⁺ T cells were memory cells or terminal effector memory cells, and the majority of activated and degranulating (CD107a⁺) HDV-specific and total CD8⁺ T cells were liver-resident (CD69⁺CXCR6⁺). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8⁺ T-cell cluster with expression of innate-like NKp30 and NKG2D receptors. The size of this population correlated with liver enzyme activity (r=1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8⁺ T-cell population suggesting global bystander activation. This was supported by the correlations between NKG2D expression and degranulation of intrahepatic CD8⁺ T cells and between frequency of degranulating CD8⁺ T cells and liver enzyme activity, and APRI score and by in vitro demonstration of cytokine-induced NKDG2D-dependent cytotoxicity.

Conclusion: Antigen-nonspecific activation of liver-resident CD8⁺ T cells may contribute to inflammation and disease stage in HDV infection.