Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B

McSharry, Brian P., Burgert, Hans-Gerhard, Owen, Douglas P., Stanton, Richard James ORCID: https://orcid.org/0000-0002-6799-1182, Prod'homme, Virginie, Sester, Martina, Koebernick, Katja, Groh, Veronika, Spies, Thomas, Cox, Steven, Little, Ann-Margaret, Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, Tomasec, Peter and Wilkinson, Gavin William Grahame ORCID: https://orcid.org/0000-0002-5623-0126 2008. Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B. Journal of Virology 82 (9) , pp. 4585-4594. 10.1128/JVI.02251-07

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Abstract

The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8+ T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology Q Science > QR Microbiology > QR355 Virology
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0022-538X/ (accessed 25/02/2014)
Publisher:	American Society for Microbiology
ISSN:	0022-538X
Date of First Compliant Deposit:	30 March 2016
Last Modified:	06 Apr 2024 17:10
URI:	https://orca.cardiff.ac.uk/id/eprint/27504

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