Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.
Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV-infected individuals; this cohort included 51 immune-activated (IA) patients, 27 immune-tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon-γ production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin-12 (IL-12), IL-15, and IL-18 in situ and lower levels of IL-10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients.


CONCLUSIONS
In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection.
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Zheng
Z
Zhang
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Shuye
S
Zhang
Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Zhengsheng
Z
Zou
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Jianfei
J
Shi
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Juanjuan
J
Zhao
Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Rong
R
Fan
Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Enqiang
E
Qin
Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Baosen
B
Li
Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
Zhiwei
Z
Li
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Xiangsheng
X
Xu
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Junliang
J
Fu
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Jiyuan
J
Zhang
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
Bin
B
Gao
Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
Zhigang
Z
Tian
Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China.
Fu-Sheng
FS
Wang
D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D005260:Female; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000473:pathology*; D008297:Male; D008875:Middle Aged
D016207:Cytokines; D007371:Interferon-gamma
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