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

Wang, E. C.Y. et al. (2018) Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses. Proceedings of the National Academy of Sciences of the United States of America, 115(19), pp. 4998-5003. (doi:10.1073/pnas.1720950115) (PMID:29691324) (PMCID:PMC5948980)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilkie, Dr Gavin and Suarez, Dr Nicolas and Lau, Dr Betty and Davison, Professor Andrew
Authors: Wang, E. C.Y., Pjechova, M., Nightingale, K., Vlahava, V.-M., Patel, M., Ruckova, E., Forbes, S. K., Nobre, L., Antrobus, R., Roberts, D., Fielding, C. A., Seirafian, S., Davies, J., Murrell, I., Lau, B., Wilkie, G. S., Suárez, N. M., Stanton, R. J., Vojtesek, B., Davison, A., Lehner, P. J., Weekes, M. P., Wilkinson, G. W.G., and Tomasec, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:24 April 2018
Copyright Holders:Copyright © 2018 National Academy of Sciences
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 115(19):4998-5003
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH