Non-selective beta-blockers reduce bystander CD8 ⁺ T cell activation in decompensated liver cirrhosis

Cirrhosis is characterized by immune dysfunction in which activated CD8⁺ T cells fuel systemic inflammation and disease progression. Non-selective beta-blockers (NSBB), widely prescribed for portal hypertension, have incompletely understood immunomodulatory effects. Here we show that CD8⁺ T cells express β2-adrenergic receptors, enriched in bystander relative to antigen-specific subsets. In vitro , the NSBB propranolol selectively suppressed cytokine-driven bystander activation, reducing CD69⁺CXCR6⁺ and NKG2D⁺ populations and pro-inflammatory cytokines, while preserving antigen-specific responses. Transcriptomic profiling after NSBB treatment revealed downregulation of interferon signaling pathway via STAT1. In paired blood and ascites samples from patients with decompensated cirrhosis (n = 31), NSBB therapy was associated with reduced bystander-activated CD8⁺ T cells. In a retrospective cohort (n = 624), NSBB therapy correlated with lower systemic and intrahepatic inflammation. These findings identify β-adrenergic blockade as a mechanism that restrains bystander CD8⁺ T cell responses without impairing antigen-specific immunity, supporting NSBB therapy as a strategy to mitigate inflammation and improve outcomes in cirrhosis.