Modulation of natural killer cells by human cytomegalovirus.
Human cytomegalovirus (HCMV) causes lifelong, persistent infections and its survival is under intense, continuous selective pressure from the immune system. A key aspect of HCMV's capacity for survival lies in immune avoidance. In this context, cells undergoing productive infection exhibit remarkable resistance to natural killer (NK) cell-mediated cytolysis in vitro. To date, six genes encoding proteins (UL16, UL18, UL40, UL83, UL141 and UL142) and one encoding a microRNA (miR-UL112) have been identified as capable of suppressing NK cell recognition. Even though HCMV infection efficiently activates expression of ligands for the NK cell activating receptor NKG2D, at least three functions (UL16, UL142 and miR-UL112) act in concert to suppress presentation of these ligands on the cell surface. Although HCMV downregulates expression of endogenous MHC-I, it encodes an MHC-I homologue (UL18) and also upregulates the expression of cellular HLA-E through the action of UL40. The disruption of normal intercellular connections exposes ligands for NK cell activating receptors on the cell surface, notably CD155. HCMV overcomes this vulnerability by encoding a function (UL141) that acts post-translationally to suppress cell surface expression of CD155. The mechanisms by which HCMV systematically evades (or, more properly, modulates) NK cell recognition constitutes an area of growing understanding that is enhancing our appreciation of the basic mechanisms of NK cell function in humans.
Wilkinson
Gavin W G
GW
Department of Medical Microbiology, Cardiff University, Tenovus Building, Heath Park, Cardiff CF14 4XX, UK. WilkinsonGW1@cardiff.ac.uk
Tomasec
Peter
P
Stanton
Richard J
RJ
Armstrong
Melanie
M
Prod'homme
Virginie
V
Aicheler
Rebecca
R
McSharry
Brian P
BP
Rickards
Carole R
CR
Cochrane
Daniel
D
Llewellyn-Lacey
Sian
S
Wang
Eddie C Y
EC
Griffin
Cora A
CA
Davison
Andrew J
AJ
D003587:Cytomegalovirus / Q000472:pathogenicity*; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C423230:ULBP2 protein, human; D014764:Viral Proteins