Liver-resident bystander CD8⁺ T cells contribute to liver disease pathogenesis in chronic hepatitis D virus infection

Question 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 responsible for the accelerated liver disease progression are unknown.

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

Results The two major innate immune cell populations in the liver, MAIT cells and NK cells, were similarly affected by HDV infection. Compared to uninfected controls, their intrahepatic frequency was decreased in HDV infection, with greater prevalence of activated and degranulating cells in the liver compared to the blood. Most CD8⁺ T-cells in the liver were activated memory or terminal effector memory cells, irrespective of HDV-specificity and viral escape, and the majority of activated and degranulated (CD107a⁺) HDV-specific and total CD8⁺ T-cells were liver-resident (CD69⁺CXCR6⁺). High-dimensionality reduction and Phenograph clustering 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 to the total intrahepatic CD8⁺ T-cell population suggesting global bystander activation. This was supported by the correlation between NKG2D⁺ total CD8⁺ T-cells and histologic activity index score, and the correlation of degranulated (CD107a⁺) total CD8⁺ T-cells with liver enzyme activity and APRI score.

Conclusion Inflammation and disease stage in HDV infection are driven by antigen-nonspecific activation of liver-resident CD8⁺ T-cells.

Publication History

Article published online:
04 January 2021