Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury.
Hackstein C-P., Spitzer J., Symeonidis K., Horvatic H., Bedke T., Steglich B., Klein S., Assmus LM., Odainic A., Szlapa J., Kessler N., Beyer M., Schmithausen R., Latz E., Flavell RA., Garbi N., Kurts C., Kümmerer BM., Trebicka J., Roers A., Huber S., Schmidt SV., Knolle PA., Abdullah Z.
BACKGROUND & AIMS: Patients with chronic liver disease (CLD) such as cirrhosis are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I Interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I for the impaired adaptive immune responses in CLD. METHODS: We combined BDL and CCl4 models of liver injury with vaccination or LCMV-infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T-cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and COVID vaccinations in CLD patients and healthy individuals in a proof-of-concept clinical study. RESULTS: We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination in mice and cirrhosis patients as well as defective T-cell responses to viral infection in mice leading to persistent infection. Innate sensing of translocated gut microbiome induced IFN-I-signalling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signalling in antigen-specific T-cells rendered them dysfunctional. Antibiotic treatment, IFNAR and IL-10Rα inhibition restored anti-viral immunity without detectable immune pathology in mice. Notably, IL-10Rα blockade restored the functional phenotype of T-cells from vaccinated cirrhosis patients. CONCLUSION: Loss of systemic T-cell immunity during prolonged liver injury is driven by IFN-/IL-10 expression induced by innate sensing of translocated microbiota. IMPACT AND IMPLICATIONS: Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hypo-responsiveness. Using different pre-clinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signalling leading to myeloid cell-induced IL-10 expression, and IL-10-signaling in antigen-specific T-cells. Given the absence of immuno-pathology after interference with IL-10R, our study highlights a novel potential target to reconstitute T-cell immunity in CLD patients that can be explored in future clinical studies.