Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients

Abstract

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. Conclusion 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.

T-cell Immunoglobulin and ITIM Domain (TIGIT) Receptor/Poliovirus Receptor (PVR) Ligand Engagement Suppresses Interferon-γ Production of Natural Killer Cells via β-Arrestin 2-mediated Negative Signaling

“…NK cell effector functions are finely tuned and timely regulated by many activating receptors and inhibitory receptors (4). Excessive NK cell activation can cause severe immunopathology of the infected tissues or autoimmune diseases (8,47). At an early stage during viral infection, NK cell-produced cytokines play a pivotal role in antiviral immunity and augment further priming of virus-specific CD8 ϩ T cell responses (8,48).…”

Immune Response in Hepatitis B Virus Infection

“…Their functionality seems often suppressed by the presence of different immunomodulatory cytokines, such as IL-10 or TGF-b (Peppa et al 2010), whereas other data have suggested an increased cytotoxic ability and involvement in liver damage (Zhang et al 2011b). One other interesting possibility is that NK cells, during chronic HBV infection, act as a rheostat of HBV-specific T cells.…”

Natural killer cells in hepatitis B virus infection

“…(2) altered expression of activating or inhibitory receptors on NK cells 33,43-46 ; (3) up-regulation of some molecules with inhibitory effects such as T cell immunoglobulin and mucin domain containing molecule-3 (Tim-3); 47 (4) maintained or even enhanced cytolytic activity, which is correlated to the severity of liver injury 33,43,46 ; and (5) impaired capacity to produce cytokines such as IFN-␥ and TNF-␣. 43,44,46,47 Viral load reduction through anti-viral therapy partly restores NK cells numbers, cytokine production and inhibitory receptor expression.…”

“…In chronic infection, NK cells display varying changes in proportion, phenotype and/or function, which differ between studies. The defects in NK cells are reflected in many aspects: (1) the percentages of hepatic and peripheral NK cells are reduced in immune-activated CHB patients, with or without changes in their subsets 33,43,44 ;…”