Rapid Antigen Processing and Presentation of a Protective and Immunodominant HLA-B*27-restricted Hepatitis C Virus-specific CD8+ T-cell Epitope

PLoS Pathogens

Stefan Tenzer¹  Paul Bowness²  Julia Schmidt³  Robert Thimme³  Astrid K. N. Iversen⁴  Hansjörg Schild⁵  Christoph Neumann-Haefelin⁵  David A. Price⁵  Ute Distler⁶  Volker Lohmann⁶  Hubert E. Blum⁷  Paul Klenerman⁸  Emma Gostick⁹ 

[1] Centre of Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany;Department of Infectious Diseases, University of Heidelberg, Heidelberg, Germany;Department of Medicine II, University Hospital Freiburg, Freiburg, Germany;Faculty of Biology, University of Freiburg, Freiburg, Germany;Institute of Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany;Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom;Nuffield Department of Clinical Medicine, Oxford, United Kingdom;Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom

关键词: Cytotoxic T cells;    T cells;    Immune response;    Antigen-presenting cells;    Cell staining;    Antigen processing;    recognition;    Proteasomes;    HIV infections;   

DOI  :  10.1371/journal.ppat.1003042

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HLA-B*27 exerts protective effects in hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. While the immunological and virological features of HLA-B*27-mediated protection are not fully understood, there is growing evidence that the presentation of specific immunodominant HLA-B*27-restricted CD8+ T-cell epitopes contributes to this phenomenon in both infections. Indeed, protection can be linked to single immunodominant CD8+ T-cell epitopes and functional constraints on escape mutations within these epitopes. To better define the immunological mechanisms underlying HLA-B*27-mediated protection in HCV infection, we analyzed the functional avidity, functional profile, antiviral efficacy and naïve precursor frequency of CD8+ T cells targeting the immunodominant HLA-B*27-restricted HCV-specific epitope as well as its antigen processing and presentation. For comparison, HLA-A*02-restricted HCV-specific epitopes were analyzed. The HLA-B*27-restricted CD8+ T-cell epitope was not superior to epitopes restricted by HLA-A*02 when considering the functional avidity, functional profile, antiviral efficacy or naïve precursor frequency. However, the peptide region containing the HLA-B*27-restricted epitope was degraded extremely fast by both the constitutive proteasome and the immunoproteasome. This efficient proteasomal processing that could be blocked by proteasome inhibitors was highly dependent on the hydrophobic regions flanking the epitope and led to rapid and abundant presentation of the epitope on the cell surface of antigen presenting cells. Our data suggest that rapid antigen processing may be a key immunological feature of this protective and immunodominant HLA-B*27-restricted HCV-specific epitope.

【 授权许可】

CC BY