期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 42, 页码 E6467-E6475出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605884113
关键词
adaptive immunity; immune evasion; herpesvirus; CD8 T cells; microRNA
资金
- Deutsche Forschungsgemeinschaft [SFB1054/TP B05, SFB1064/TP A13, SFB-TR36/TP A04]
- Deutsche Krebshilfe [107277, 109661]
- National Cancer Institute [CA70723, CA022443]
- Deutscher Akademischer Austauschdienst (DAAD, Studienstipendien fur auslandische Graduierte aller wissenschaftlichen Facher)
- European Molecular Biology Organization (EMBO)
Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4(+) T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated-whether EBV miRNAs also counteract surveillance by CD8(+) T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8(+) T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8(+) T cells. Moreover, miRNA-mediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8(+) T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4(+) but also by antiviral CD8(+) T cells.
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