Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury

Area of Science:

• Immunology
• Hepatology
• Microbiology

Background:

• Chronic liver disease (CLD) and cirrhosis increase susceptibility to infections and reduce vaccine effectiveness.
• Microbial translocation and elevated type I interferon (IFN-I) are key features of CLD.
• The role of microbiota-induced IFN-I in impaired adaptive immunity in CLD remains unclear.

Purpose of the Study:

• To investigate the impact of microbiota-induced IFN-I on adaptive immune responses in CLD.
• To elucidate the mechanisms underlying impaired T-cell immunity and vaccine hyporesponsiveness in CLD.

Main Methods:

• Utilized mouse models of chronic liver injury (bile duct ligation and carbon tetrachloride).
• Employed genetic modifications (IFNAR, IL-10, IL-10R knockout models) and pharmacological interventions (anti-IFNAR, anti-IL-10R antibodies).
• Assessed T-cell responses and antibody titers post-vaccination or viral infection in mice and patients with CLD.

Main Results:

• Prolonged liver injury impaired T-cell responses to vaccination and viral infection in mice, causing persistent infections.
• Patients with cirrhosis exhibited defective T-cell responses to vaccination.
• Microbiota sensing induced IFN-I signaling, leading to IL-10 production and T-cell dysfunction via IL-10 receptor (IL-10R) signaling; blockade restored immunity.

Conclusions:

• Microbiota-induced IFN-I and subsequent IL-10 signaling drive T-cell immune loss in chronic liver injury.
• Targeting the IL-10R pathway offers a potential strategy to restore T-cell immunity in CLD patients.
• This approach shows promise for improving vaccine efficacy and combating infections in individuals with chronic liver disease.