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

Prod'homme, Virginie ORCID: https://orcid.org/0000-0002-9664-4710, Griffin, Cora, Aicheler, Rebecca, Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, McSharry, Brian Patrick, Rickards, Carole Ruth, Stanton, Richard James ORCID: https://orcid.org/0000-0002-6799-1182, Borysiewicz, Leszek K., Lopez-Botet, Miguel, Wilkinson, Gavin William Grahame ORCID: https://orcid.org/0000-0002-5623-0126 and Tomasec, Peter 2007. The Human Cytomegalovirus MHC Class I Homolog UL18 Inhibits LIR-1+ but Activates LIR-1- NK Cells. The Journal of Immunology 178 (7) , pp. 4473-4481.

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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 (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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	17 Oct 2022 08:29
URI:	https://orca.cardiff.ac.uk/id/eprint/294

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