The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells.
The inhibitory leukocyte Ig-like receptor 1 (LIR-1, also known as ILT2, CD85j, or LILRB1) was identified by its high affinity for the human CMV (HCMV) MHC class I homolog gpUL18. The role of this LIR-1-gpUL18 interaction in modulating NK recognition during HCMV infection has previously not been clearly defined. In this study, LIR-1(+) NKL cell-mediated cytotoxicity was shown to be inhibited by transduction of targets with a replication-deficient adenovirus vector encoding UL18 (RAd-UL18). Fibroblasts infected with an HCMV UL18 mutant (DeltaUL18) also exhibited enhanced susceptibility to NKL killing relative to cells infected with the parental virus. In additional cytolysis assays, UL18-mediated protection was also evident in the context of adenovirus vector transduction and HCMV infection of autologous fibroblast targets using IFN-alpha-activated NK bulk cultures derived from a donor with a high frequency of LIR-1(+) NK cells. A single LIR-1(high) NK clone derived from this donor was inhibited by UL18, while 3 of 24 clones were activated. CD107 mobilization assays revealed that LIR-1(+) NK cells were consistently inhibited by UL18 in all tested donors, but this effect was often masked in the global response by UL18-mediated activation of a subset of LIR-1(-) NK cells. Although Ab-blocking experiments support UL18 inhibition being induced by a direct interaction with LIR-1, the UL18-mediated activation is LIR-1 independent.
Prod'homme
Virginie
V
Department of Medical Microbiology, Cardiff University, Heath Park, Cardiff, Wales, UK.
Griffin
Cora
C
Aicheler
Rebecca J
RJ
Wang
Eddie C Y
EC
McSharry
Brian P
BP
Rickards
Carole R
CR
Stanton
Richard J
RJ
Borysiewicz
Leszek K
LK
López-Botet
Miguel
M
Wilkinson
Gavin W G
GW
Tomasec
Peter
P
D000256:Adenoviridae / Q000235:genetics; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008213:Lymphocyte Activation; D011971:Receptors, Immunologic / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000276:immunology; D017384:Sequence Deletion
D015703:Antigens, CD; D036022:Capsid Proteins; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; C079750:VP23 protein, Human herpesvirus 1