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

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• 作者：Katharina Esser-Nobis¹ ; Julia Schmidt² ; Katja Nitschke² ; Christoph Neumann-Haefelin² ; Robert Thimme² ; Volker Lohmann¹ ; ^{Volker_lohmann@med.uni-heidelberg.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCV ; hepatitis C virus ; CsA ; cyclosporine A ; MHC ; major histocompatibility complex ; Cyp ; cyclophilin ; E ; T ratio ; effector-to-target ratio ; NS5BEM ; epitope-matched HCV non-structural protein 5B ; IFN ; interferon ; b2m ; beta-2 microglobulin ; GLuc ; Gaussia-luciferase ; TFR ; transferrin receptor ; ERAP1 ; endoplasmic reticulum aminopeptidase 1 ; SFA ; sanglifehrin A ; CsH ; cyclosporine H ; TCR ; T cell receptor ; GeoMFI ; geometric mean fluorescence intensity
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1305-1314
• 全文大小：1958 K

文摘

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.

ec_2">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.

ec_3">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.

ec_4">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.