Entecavir‐induced interferon‐λ1 suppresses type 2 innate lymphoid cells in patients with hepatitis B virus‐related liver cirrhosis

• Published in: Journal of viral hepatitis Vol. 28; no. 5; pp. 795 - 808
• Main Authors: Wang, Si‐Qi, Shen, Yue, Li, Jing, Liu, Yun, Cheng, Li‐Sha, Wu, Sheng‐Di, She, Wei‐Min, Jiang, Wei
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.05.2021
• Subjects: Antiviral drugs; Cell culture; chronic hepatitis B; Cirrhosis; Cytokines; Dendritic cells; entecavir; Hepatitis B; Homeostasis; Immunomodulation; Interferon; interferon‐λ1; Leukocytes (mononuclear); Liver cirrhosis; Liver diseases; Lymphoid cells; Natural killer cells; Patients; Peripheral blood mononuclear cells; Tumor necrosis factor; type 2 innate lymphoid cells; chronic hepatitis B; entecavir; type 2 innate lymphoid cells; interferon-λ1; liver cirrhosis
• ISSN: 1352-0504; 1365-2893; 1365-2893
• DOI: 10.1111/jvh.13476

The immunomodulatory effects of entecavir (ETV) in anti‐hepatitis B virus (HBV) therapy have long been recognized. This study aimed to determine the effects of ETV on non‐natural killer innate lymphoid cells (non‐NK ILCs) in HBV‐related liver disease progression. We enrolled treatment‐naïve chronic hepatitis B (CHB) and HBV‐related liver cirrhosis (LC) patients treated with ETV for 24 months. Before and after therapy, the frequency and cytokine profiles of ILC2s and non‐NK ILCs subset homeostasis and their clinical significance were determined, and serial serum interferon (IFN)‐λ levels were analysed. Peripheral blood mononuclear cells (PBMCs) of untreated LC patients were cultured with serum from untreated and ETV‐treated LC patients in addition to being subject to IFN‐λ1 neutralization and stimulation, and the frequency and cytokine production of ILC2s as well as non‐NK ILCs subset ratios were calculated. Furthermore, IFN‐λ receptor expression on non‐NK ILCs and dendritic cells (DCs) was measured. After 24 months of ETV treatment, the frequency and cytokine production of ILC2s (IL‐4, IL‐13, IFN‐γ, TNF‐α) decreased with increased ILC1/ILC2 and decreased ILC2/ILC3 ratios, revealing a close association with disease status in LC patients. Long‐term ETV administration‐induced serum IFN‐λ1 levels were negatively correlated with ILC2s. ETV‐treated LC serum culture and IFN‐λ1 stimulation yielded similar effects on suppression of ILC2s, and IFN‐λ1 neutralization in serum culture partly inhibited this effect. The IFN‐λ receptor was detected on DCs but not on non‐NK ILCs. In conclusion, ETV suppresses the frequency and cytokine profiles of ILC2s by increasing IFN‐λ1 in LC patients.