Shin, E.-C. | bioRxiv Science

bioRxiv2025

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

immunology↗

bioRxiv2025

TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+ T cells

Here we investigated the regulatory mechanisms of TCR-independent bystander activation and NK-like cytotoxicity of human memory CD8+ T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8+ T-cell activation, including increased NKG2D expression and upregulation of genes related to NK cytotoxicity and IFN response. Moreover, ionomycin suppressed IL-15-induced bystander activation and NK-like cytotoxicity, indicating that Ca2+-calcineurin signaling is responsible for TCR-mediated suppression of IL-15-induced bystander activation. In detail, NFATc1 suppressed IL-15-induced bystander activation via binding to AP-1 that is necessary for the IL-15-induced upregulation of NK cytotoxicity-related genes. Consistent with these results, calcineurin inhibitors enhanced IL-15-induced NKG2D expression in the presence of TCR signals. Additionally, we defined genes upregulated by IL-15 and downregulated by concurrent TCR signals as an IL-15-induced bystander activation gene set, and found that this gene signature was upregulated in bystander CD8+ T cells from patients with hepatitis A virus infection. This study paves the way for further investigation of bystander CD8+ T-cell activation in various pathological conditions, and its regulation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/632884v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1e6c320org.highwire.dtl.DTLVardef@114a23eorg.highwire.dtl.DTLVardef@1a7b9edorg.highwire.dtl.DTLVardef@9faccc_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITCR signaling downregulates IL-15-induced transcriptomic features related to NK-like bystander activation of human memory CD8+ T cells via the Ca2+-calcineurin pathway. C_LIO_LINFATc1 suppresses IL-15-induced bystander activation via binding to AP-1, which is responsible for IL-15-induced NK-like cytotoxic activity. C_LIO_LICalcineurin inhibitors cannot suppress IL-15-induced bystander CD8+ T-cell activation, and paradoxically increase IL-15-induced NKG2D expression in the presence of TCR signals. C_LIO_LIGenes upregulated by IL-15 and downregulated by concurrent TCR signals define the gene set of bystander CD8+ T-cell activation, which was validated in disease contexts. C_LI

immunology↗