AccScience Publishing / MI / Online First / DOI: 10.36922/MI025360095
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ORIGINAL RESEARCH ARTICLE

Hyporesponsiveness to pathogen stimulation in CD56+ natural killer cells and CD8+ T cells from patients with primary sclerosing cholangitis

Sandra Kalthoff1 ,  Leona Dold1,2 ,  Jessica Wolf1,2 ,  Christian P. Strassburg1 ,  Bettina Langhans1,2*
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1 Department of Internal Medicine I, University Hospital of Bonn, Venusberg-Campus 1, Bonn, North Rhine-Westphalia, Germany
2 German Center for Infection Research, Partner Site Cologne-Bonn, Bonn, North Rhine-Westphalia, Germany
MI, 025360095 https://doi.org/10.36922/MI025360095
Received: 1 September 2025 | Revised: 27 November 2025 | Accepted: 15 December 2025 | Published online: 6 January 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive inflammation of the intra- and extrahepatic bile ducts and a high association with inflammatory bowel disease. Since bacterial and viral stimuli are thought to contribute to the pathogenesis of autoimmune diseases, our study aims to investigate the effects of synthetic pathogenic agonists on the cytotoxic function of cluster of differentiation (CD)56+ natural killer (NK) cells and CD8+ T cells in PSC. A total of 17 PSC patients, 18 autoimmune hepatitis (AIH) patients, and 14 healthy controls (HCs) were included in this study. Using multicolor flow cytometry, we analyzed cytotoxic activity (CD107a assay) and secretion of interferon-gamma and tumor necrosis factor-alpha in peripheral CD56+ NK-cell subsets and CD8+ T cells after in vitro stimulation with synthetic bacterial (Pam3CSK, lipopolysaccharide [LPS], CpG-ODN-2216, and flagellin) and viral agonists (polyinosinic: polycytidylic acid [poly(I: C)], poly(I: C)-high molecular weight/LyoVec™, 5’ppp-dsRNA/LyoVec™, and R837). Compared with AIH patients and HCs, CD56+ NK-cell subsets from PSC patients showed reduced cytotoxicity both at baseline and upon in vitro stimulation with synthetic bacterial/viral agonists. Notably, the percentage of unstimulated CD107a+CD56dimCD16+ NK cells positively correlated with clinical serum parameters in PSC. In addition, the percentage of CD107a+CD8+ cells was significantly reduced after synthetic bacterial/viral stimulation in PSC patients. Finally, in PSC patients, production of pro-inflammatory cytokines was markedly reduced in CD56highCD16− NK cells upon in vitro stimulation with Pam3CSK and LPS, respectively. This hyporesponsiveness of CD56+ NK cells and CD8+ T cells may contribute to the development of hepatic inflammation, representing a hallmark of PSC pathogenesis.

Keywords
Primary sclerosing cholangitis
Autoimmune liver disease
Synthetic bacterial/viral agonists
CD56+ natural killer cells
CD8+ T cells
Cytotoxicity
Cytokine production
Funding
The study was funded by the German Center for Infection Research (DZIF; TI 07.003-MD program).
Conflict of interest
The authors declare they have no competing interests.
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