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Department of
* Medical Microbiology and
Department of Medical Biochemistry and Immunology, Cardiff University, Cardiff, United Kingdom;
Imperial College, London, United Kingdom; and
Department of Experimental and Health Sciences, Molecular Immunopathology Unit, Universitat Pompeu Fabra, Barcelona, Spain
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 (
UL18) 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-
-activated NK bulk cultures derived from a donor with a high frequency of LIR-1+ NK cells. A single LIR-1high 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funds from the Wellcome Trust and the Biotechnology and Biological Sciences Research Council. M.L.-B. is supported by the Spanish Ministry of Education and Science (SAF2004-07632).
2 V.P. and C.G. are joint first authors.
3 Current address: Anthony Nolan Research Institute, The Royal Free Hospital, Pond Street, Hampstead, London, U.K.
4 Address correspondence and reprint requests to Prof. Gavin G. W. Wilkinson, Department of Medical Microbiology, Cardiff University, Tenovus Building, Heath Park, Cardiff, U.K. E-mail address: wilkinsongw1{at}cf.ac.uk
5 Abbreviations used in this paper: HCMV, human CMV; MCMV, murine CMV; MIC, MHC class I-related chain; ULBP, U16-binding protein; RAET, retinoic acid early transport; ORF, open reading frame; LIR-1, leukocyte Ig-like receptor 1; RAd, replication-deficient adenovirus; HFFF, human fetal foreskin fibroblast; MFI, mean fluorescence intensity; Ctrl, control.
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