The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8+ T cell activation

• Verfasst von: Esser-Nobis, Katharina [VerfasserIn]
• Verfasst von: Schmidt, Julia [VerfasserIn]
• Verfasst von: Nitschke, Katja [VerfasserIn]
• Verfasst von: Neumann-Haefelin, Christoph [VerfasserIn]
• Verfasst von: Thimme, Robert [VerfasserIn]
• Verfasst von: Lohmann, Volker [VerfasserIn]
• Titel: The cyclophilin-inhibitor alisporivir stimulates antigen presentation thereby promoting antigen-specific CD8+ T cell activation
• Verf.angabe: Katharina Esser-Nobis, Julia Schmidt, Katja Nitschke, Christoph Neumann-Haefelin, Robert Thimme, Volker Lohmann
• E-Jahr: 2016
• Jahr: 26 February 2016
• Umfang: 10 S.
• Fussnoten: Im Titel ist "+" hochgestellt ; Gesehen am 11.05.2020
• Titel Quelle: Enthalten in: Journal of hepatology
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1985
• Jahr Quelle: 2016
• Band/Heft Quelle: 64(2016), 6, Seite 1305-1314
• ISSN Quelle: 1600-0641
• DOI: doi:10.1016/j.jhep.2016.02.027
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antigen presentation
• Sach-SW: Cyclophilin
• Sach-SW: Cyclosporine A
• Sach-SW: Debio025
• Sach-SW: HCV
• Sach-SW: MHC-I
• K10plus-PPN: 1697814271

Abstract

Background & Aims - Cyclophilin-inhibitors have potent antiviral activity against Hepatitis C virus (HCV) and are promising candidates for broad-spectrum antiviral therapy. Cyclosporine A (CsA) acts immunosuppressive by blocking T cell activation and antigen presentation. Alisporivir, a non-immunosuppressive CsA analog in clinical development, does not inhibit T cell activation. In this study we explored the impact of alisporivir on antigen presentation. - Methods - Hepatoma cells endogenously expressing the epitope-restricting major histocompatibility complex-class I (MHC-I) allele HLA-A2 and constitutively expressing a viral antigen were established to study the impact of cyclophilin-inhibitors on antigen presentation. Antigen-specific CD8+ T cell activation and MHC-I surface expression were measured to quantify antigen presentation. - Results - Our work establishes a novel cell culture model to study antigen presentation in liver-derived cells. Authentic regulation of antigen presentation was ensured by the action of pro- and anti-inflammatory cytokines. Alisporivir pretreatment stimulated antigen presentation by hepatoma target cells, leading to enhancement of antigen-specific CD8+ T cell activation by 40%. Alisporivir, as well as a panel of other cyclophilin-inhibitors, induced an increase of MHC-I and beta-2 microglobulin on the surface of several cell lines. The drug neither enhanced MHC-I transcript or protein levels nor affected surface expression of other proteins or protein trafficking in general. Proteasome-inhibitors completely blocked the alisporivir-directed enhancement of surface MHC-I, suggesting an influence of the drug on peptide-availability. - Conclusions - Alisporivir stimulates antigen presentation by inducing enhanced MHC-I surface expression, thereby promoting antigen-specific CD8+ T cell activation. This immunostimulatory function might further contribute to the antiviral activity of non-immunosuppressive cyclophilin-inhibitors.