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bioRxiv · 10.1101/2025.11.18.688703

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

Lietzau, A.·Tapken, I.·Kim, S.-Y.·Souleiman, R.·Freyer, E.·Kraft, A. R.·Schuette, S.·Tergast, T. L.·Maasoumy, B.·Wedemeyer, H.·Drath, I.·Zurek, G.·Shin, E.-C.·Cornberg, M.·Niehaus, C.
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Abstract

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

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Lietzau, A., Tapken, I., Kim, S.-Y., Souleiman, R., Freyer, E., Kraft, A. R., Schuette, S., Tergast, T. L., Maasoumy, B., Wedemeyer, H., Drath, I., Zurek, G., Shin, E.-C., Cornberg, M., Niehaus, C.. 2025-11-18. Non-selective beta blockers reduce bystander CD8+ T cell activation in decompensated liver cirrhosis. https://doi.org/10.1101/2025.11.18.688703

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