Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4.
Epstein-Barr virus (EBV) is a tumorigenic human herpesvirus that persists for life in healthy immunocompetent carriers. The viral strategies that prevent its clearance and allow reactivation in the face of persistent immunity are not well understood. Here we demonstrate that EBV infection of monocytes inhibits their development into dendritic cells (DCs), leading to an abnormal cellular response to granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) and to apoptotic death. This proapoptotic activity was not affected by UV inactivation and was neutralized by EBV antibody-positive human sera, indicating that binding of the virus to monocytes is sufficient to alter their response to the cytokines. Experiments with the relevant blocking antibodies or with mutated EBV strains lacking either the EBV envelope glycoprotein gp42 or gp85 demonstrated that interaction of the trimolecular gp25-gp42-gp85 complex with the monocyte membrane is required for the effect. Our data provide the first evidence that EBV can prevent the development of DCs through a mechanism that appears to bypass the requirement for viral gene expression, and they suggest a new strategy for interference with the function of DCs during the initiation and maintenance of virus-specific immune responses.
Li
LiQi
L
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
Liu
Daorong
D
Hutt-Fletcher
Lindsey
L
Morgan
Andrew
A
Masucci
Maria G
MG
Levitsky
Victor
V
D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation; D008561:Membrane Fusion; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D012367:RNA, Viral / Q000032:analysis; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D014759:Viral Envelope Proteins / Q000494:pharmacology
D006133:Growth Substances; D012367:RNA, Viral; D014759:Viral Envelope Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor