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J Exp Med. 2016 Sep 19;213(10):2065-80. doi: 10.1084/jem.20160248. Epub 2016 Sep 12.

Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing.

Author information

1
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Partner site Munich, Germany, D-81377 Munich, Germany German Centre for Infection Research (DZIF), Partner site Munich, Germany, D-81377 Munich, Germany.
2
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Partner site Munich, Germany, D-81377 Munich, Germany German Centre for Infection Research (DZIF), Partner site Munich, Germany, D-81377 Munich, Germany Children's Hospital, Technical University Munich, D-80337 Munich, Germany.
3
Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health Munich, University of Munich, D-80539 Munich, Germany Institute for Immunology, University of Munich, D-80539 Munich, Germany.
4
Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, D-80337 Munich, Germany.
5
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Munich, Germany.
6
Institute of Bioinformatics and System Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Munich, Germany.
7
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706.
8
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Partner site Munich, Germany, D-81377 Munich, Germany German Centre for Infection Research (DZIF), Partner site Munich, Germany, D-81377 Munich, Germany hammerschmidt@helmholtz-muenchen.de.

Abstract

Epstein-Barr virus (EBV) is a tumor virus that establishes lifelong infection in most of humanity, despite eliciting strong and stable virus-specific immune responses. EBV encodes at least 44 miRNAs, most of them with unknown function. Here, we show that multiple EBV miRNAs modulate immune recognition of recently infected primary B cells, EBV's natural target cells. EBV miRNAs collectively and specifically suppress release of proinflammatory cytokines such as IL-12, repress differentiation of naive CD4(+) T cells to Th1 cells, interfere with peptide processing and presentation on HLA class II, and thus reduce activation of cytotoxic EBV-specific CD4(+) effector T cells and killing of infected B cells. Our findings identify a previously unknown viral strategy of immune evasion. By rapidly expressing multiple miRNAs, which are themselves nonimmunogenic, EBV counteracts recognition by CD4(+) T cells and establishes a program of reduced immunogenicity in recently infected B cells, allowing the virus to express viral proteins required for establishment of life-long infection.

PMID:
27621419
PMCID:
PMC5030804
DOI:
10.1084/jem.20160248
[Indexed for MEDLINE]
Free PMC Article

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