The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells

Virginie Prod'homme, Cora Griffin, Rebecca J. Aicheler, Eddie C.Y. Wang, Brian P. McSharry, Carole R. Rickards, Richard J. Stanton, Leszek K. Borysiewicz, Miguel López-Botet, Gavin W.G. Wilkinson, Peter Tomasec

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108 Citations (Scopus)

Abstract

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 (AUL18) 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 adenoviros vector transduction and HCMV infection of autologous fibroblast targets using IFN-α-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.

Original languageEnglish
Pages (from-to)4473-4481
Number of pages9
JournalJournal of Immunology
Volume178
Issue number7
DOIs
Publication statusPublished - 01 Apr 2007

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