Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing.
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.
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.
Takanobu
0000-0001-8637-2996
T
Tagawa
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.
Manuel
0000-0002-4614-7599
M
Albanese
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.
Mickaël
0000-0001-6541-689X
M
Bouvet
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.
Andreas
A
Moosmann
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.
Josef
J
Mautner
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.
Vigo
0000-0002-4659-0427
V
Heissmeyer
Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, D-80337 Munich, Germany.
Christina
C
Zielinski
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Munich, Germany.
Dominik
0000-0002-8800-0683
D
Lutter
Institute of Bioinformatics and System Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Munich, Germany.
Jonathan
0000-0002-6126-9287
J
Hoser
Institute of Bioinformatics and System Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Munich, Germany.
Maximilian
0000-0003-3288-4229
M
Hastreiter
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706.
Mitch
0000-0002-2736-6542
M
Hayes
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706.
Bill
0000-0002-8724-4504
B
Sugden
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.
Wolfgang
0000-0002-4659-0427
W
Hammerschmidt
D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007109:Immunity; D018836:Inflammation Mediators / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013045:Species Specificity; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D035683:MicroRNAs; D010455:Peptides; D011956:Receptors, Cell Surface; D018664:Interleukin-12