INTRODUCTION
Natural killer (NK) cells are central players in antiviral immunity, exerting cytotoxic effects on infected cells and secreting cytokines that shape adaptive responses. In the context of chronic viral infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), their activity is modulated by diverse molecular signals, most notably type-I interferons (IFNs). While robust IFN signatures are a hallmark of chronic HCV, similar NK cell functional alterations are observed in HBV, highlighting the complexity of immune regulation beyond IFN-driven mechanisms. Understanding these shared and distinct pathways offers a foundation for therapeutic innovation.
TYPE-I INTERFERONS AND NK CELL MODULATION
Type-I IFNs are potent regulators of innate immunity and critical modulators of NK cell function during viral infection. In HCV, persistent IFN signaling enhances NK cell cytotoxicity while impairing cytokine release, contributing to disease persistence and immune evasion. Interestingly, comparable NK cell behavior in HBV infection occurs without a pronounced IFN milieu, suggesting IFN-independent regulatory layers. Dissecting the dual role of IFNs—protective versus suppressive—remains a critical area of research with implications for antiviral therapy.
INTERFERON-STIMULATED GENES IN NK CELL FUNCTION
Conserved interferon-stimulated genes (ISGs) such as IFITM3, IRF1, IFIT2, and ISG20 exhibit strong expression in NK cells across healthy donors and patients with chronic HBV or HCV. Their consistent expression patterns, regardless of IFN levels, indicate that these ISGs are integral to NK cell biology rather than simply markers of viral persistence. Functional studies suggest these ISGs contribute not only to direct antiviral defense but also to regulatory mechanisms that balance NK cytotoxicity and cytokine production.
TRANSCRIPTION FACTORS GOVERNING NK CELL DIFFERENTIATION
The expression of NK cell ISGs is tightly linked to differentiation states and governed by transcription factors such as ETS1, FLI1, and Eomes. These fate-determining regulators ensure that NK cells adapt to environmental cues and maintain functional readiness against viral challenges. Deciphering their role in ISG regulation provides insight into how NK cells achieve both short-term effector responses and long-term adaptation during chronic infections.
NETWORK ANALYSIS OF NK CELL ISGs
Systems-level network analysis reveals that NK cell ISGs extend their function beyond antiviral defense to roles in cellular transport, metabolic regulation, and survival pathways. This broad repertoire highlights the integration of immune function with metabolic adaptation in the chronic infection setting. By identifying key ISG-driven hubs, researchers can better understand how NK cells maintain activity in resource-limited or suppressive environments such as chronic HBV and HCV infections.
IMPLICATIONS FOR IMMUNOTHERAPY
The constitutive expression of ISGs in NK cells, independent of persistent IFN signaling, underscores new therapeutic opportunities for modulating immune responses. Targeting transcription factors or metabolic pathways linked with ISG activity may restore balanced NK function, enabling effective viral control without promoting immune exhaustion. These findings provide a roadmap for developing immunotherapies aimed at enhancing NK cell responses in chronic viral infections and potentially in cancer immunology.
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