The Human Cytomegalovirus MHC Class I Homolog UL18 Inhibits LIR-1+ but Activates LIR-1− NK Cells1

• Published in: The Journal of immunology (1950) Vol. 178; no. 7; pp. 4473 - 4481
• Main Authors: Prod’homme, Virginie, Griffin, Cora, Aicheler, Rebecca J., Wang, Eddie C. Y., McSharry, Brian P., Rickards, Carole R., Stanton, Richard J., Borysiewicz, Leszek K., López-Botet, Miguel, Wilkinson, Gavin W. G., Tomasec, Peter
• Format: Journal Article
• Language: English
• Published: 01.04.2007
• ISSN: 0022-1767; 1550-6606

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 (ΔUL18) 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- α -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.