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 {beta}2-adrenergic receptors, enriched in bystander relative to antigen-specific subsets. In vitro, the NSBB propranolol selectively suppressed cytokine-driven bystander activation, reducing CD69CXCR6 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 {beta}-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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/688703v1_ufig1.gif" ALT="Figure 1000"> View larger version (29K): org.highwire.dtl.DTLVardef@191c6dcorg.highwire.dtl.DTLVardef@196aef0org.highwire.dtl.DTLVardef@1b73c83org.highwire.dtl.DTLVardef@e5d6fb_HPS_FORMAT_FIGEXP M_FIG C_FIG