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Downregulation of natural killer cell–activating ligand CD155 by human cytomegalovirus UL141

Nature Immunology volume 6, pages 181–188 (2005)Cite this article

Abstract

Natural killer (NK) cells are crucial in the control of cytomegalovirus infections in mice and humans. Here we show that the viral UL141 gene product has an immunomodulatory function that is associated with low-passage strains of human cytomegalovirus. UL141 mediated efficient protection of cells against killing by a wide range of human NK cell populations, including interferon-α-stimulated bulk cultures, polyclonal NK cell lines and most NK cell clones tested. Evasion of NK cell killing was mediated by UL141 blocking surface expression of CD155, which was previously identified as a ligand for NK cell-activating receptors CD226 (DNAM-1) and CD96 (TACTILE). The breadth of the UL141-mediated effect indicates that CD155 has a key role in regulating NK cell function.

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Figure 1: Resistance to NK cell attack maps to the HCMV UL/b′ sequence.
Figure 2: UL141 induces protection against NK cell attack.
Figure 3: Characterization of gpUL141 expression.
Figure 4: UL141-mediated downregulation of cell surface CD155 detected by flow cytometry.
Figure 5: UL141-mediated downregulation of cell surface CD155 detected by fluorescence microscopy.
Figure 6: UL141 inhibits maturation of CD155.

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Acknowledgements

We thank C. Jones and D. Kipling for their cooperation with the telomerase immortalization of fibroblasts; V. Groh for MIC mAbs; O. Mandelboim for NKp30-Fc and NKp46-Fc proteins; and E. Mocarski, M. Wills and J. Sathish for discussions. Supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council and Medical Research Council.

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Author notes

  1. Peter Tomasec and Eddie C Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Section of Infection and Immunity, Tenovus Building, College of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XX, UK

    Peter Tomasec, Eddie C Y Wang, Melanie Armstrong, Cora Griffin, Brian P McSharry, Rebecca J Morris, Sian Llewellyn-Lacey, Carole Rickards & Gavin W G Wilkinson

  2. Medical Research Council Virology Unit, Institute of Virology, Glasgow, G11 5JR, UK

    Andrew J Davison

  3. Masaryk Memorial Cancer Institute, Brno, 656 53, Czech Republic

    Borivoj Vojtesek

  4. Department of Microbiology, Graduate School of Medicine, University of Tokyo, Japan

    Akio Nomoto

  5. Medical Virology, University of Tubingen, Tubingen, Germany

    Christian Sinzger

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Correspondence to Gavin W G Wilkinson.

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Supplementary information

Supplementary Fig. 1

Amino acid sequence alignment of UL141 from 23 HCMV strains allowing a high degree of conservation. (PDF 69 kb)

Supplementary Fig. 2

Ig-like b sandwich domains encoded by HCMV UL141 (residues 15-114 in the mature protein), its orthologues in chimpanzee and rhesus cytomegalovirus (CCMV and RhCMV UL141), and the related UL14 gene in HCMV and CCMV. (PDF 54 kb)

Supplementary Fig. 3

Expression of a Secreted form of gpUL141. (PDF 138 kb)

Supplementary Fig. 4

GpUL141 is expressed with early-late phase kinetics. (PDF 47 kb)

Supplementary Fig. 5

Analysis of intracellular localization of gpUL141. (PDF 231 kb)

Supplementary Fig. 6

NK killing of autologous strain TB40E-Bart-infected fibroblasts is inhibited by treatment with the anti-CD155 mAb D171. (PDF 53 kb)

Supplementary Fig. 7

UL141, but not UL144 or UL145, inhibited expression of CD155 on stably transfected HEK-293 cells. (PDF 46 kb)

Supplementary Fig. 8

Pre-treatment with soluble UL141 blocks binding of the CD155 mAb D171. (PDF 59 kb)

Supplementary Fig. 9

Adhesion between NK cells and targets expression UL141. (PDF 99 kb)

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Tomasec, P., Wang, E., Davison, A. et al. Downregulation of natural killer cell–activating ligand CD155 by human cytomegalovirus UL141. Nat Immunol 6, 181–188 (2005). https://doi.org/10.1038/ni1156

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