Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells.
Dendritic cells (DCs) play a pivotal role in the generation of virus-specific cytotoxic T-cell responses, but some viruses can render DCs inefficient in stimulating T cells. We studied whether infection of DCs with human cytomegalovirus (HCMV) results in a suppression of DC function which may assist HCMV in establishing persistence. The effect of HCMV infection on the phenotype and function of monocyte-derived DCs and on their ability to mature following infection with an endothelial cell-adapted clinical HCMV isolate were studied. HCMV infection induced no maturation of DCs; instead, it efficiently down-regulated the expression of surface major histocompatibility complex (MHC) class I, CD40, and CD80 molecules. Slight down-regulation of MHC class II and CD86 molecules was also observed. Lipopolysaccharide (LPS)-induced maturation of infected DCs was strongly inhibited, as indicated by lower levels of surface expression of MHC class I, class II, costimulatory, and CD83 molecules. The down-regulation or inhibition of these surface markers occurred only in HCMV antigen-positive DCs. DCs produced no interleukin 12 (IL-12) and only low levels of tumor necrosis factor alpha (TNF-alpha) upon HCMV infection. Furthermore, cytokine production upon stimulation with LPS or CD40L was significantly impaired. Inhibition of cytokine production did not depend on viral gene expression as UV-irradiated HCMV resulted in the same effect. Proliferation and cytotoxicity of T cells specific to a recall antigen presented by DCs were also reduced when DCs were HCMV infected. This study shows that HCMV inhibits DC function, revealing a powerful viral strategy to delay or prevent the generation of virus-specific cytotoxic T cells.
Moutaftsi
Magdalena
M
Section of Infection and Immunity, University of Wales College of Medicine, Cardiff, United Kingdom.
Mehl
Anja M
AM
Borysiewicz
Leszek K
LK
Tabi
Zsuzsanna
Z
D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D015536:Down-Regulation; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D016207:Cytokines; D006680:HLA Antigens; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12