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Proc Natl Acad Sci U S A. 2018 May 8;115(19):4998-5003. doi: 10.1073/pnas.1720950115. Epub 2018 Apr 24.

Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses.

Author information

1
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; wangec@cf.ac.uk.
2
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
3
Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic.
4
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
5
Institute of Infection, Immunity & Inflammation, Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom.

Abstract

CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMV∆UL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMV∆UL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors.

KEYWORDS:

CD58; CTLs; NK cells; human cytomegalovirus; immune modulation

PMID:
29691324
PMCID:
PMC5948980
DOI:
10.1073/pnas.1720950115
[Indexed for MEDLINE]
Free PMC Article

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