Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation

Ashley, Caroline L., McSharry, Brian P., McWilliam, Hamish E. G., Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182, Fielding, Ceri A. ORCID: https://orcid.org/0000-0002-5817-3153, Mathias, Rommel A., Fairlie, David P., McCluskey, James, Villadangos, Jose A., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Abendroth, Allison and Slobedman, Barry 2023. Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation. Frontiers in Immunology 14 10.3389/fimmu.2023.1107497

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Abstract

Introduction: The antigen presentation molecule MHC class I related protein-1 (MR1) is best characterized by its ability to present bacterially derived metabolites of vitamin B2 biosynthesis to mucosal-associated invariant T-cells (MAIT cells). Methods: Through in vitro human cytomegalovirus (HCMV) infection in the presence of MR1 ligand we investigate the modulation of MR1 expression. Using coimmunoprecipitation, mass spectrometry, expression by recombinant adenovirus and HCMV deletion mutants we investigate HCMV gpUS9 and its family members as potential regulators of MR1 expression. The functional consequences of MR1 modulation by HCMV infection are explored in coculture activation assays with either Jurkat cells engineered to express the MAIT cell TCR or primary MAIT cells. MR1 dependence in these activation assays is established by addition of MR1 neutralizing antibody and CRISPR/Cas-9 mediated MR1 knockout. Results: Here we demonstrate that HCMV infection efficiently suppresses MR1 surface expression and reduces total MR1 protein levels. Expression of the viral glycoprotein gpUS9 in isolation could reduce both cell surface and total MR1 levels, with analysis of a specific US9 HCMV deletion mutant suggesting that the virus can target MR1 using multiple mechanisms. Functional assays with primary MAIT cells demonstrated the ability of HCMV infection to inhibit bacterially driven, MR1-dependent activation using both neutralizing antibodies and engineered MR1 knockout cells. Discussion: This study identifies a strategy encoded by HCMV to disrupt the MR1:MAIT cell axis. This immune axis is less well characterized in the context of viral infection. HCMV encodes hundreds of proteins, some of which regulate the expression of antigen presentation molecules. However the ability of this virus to regulate the MR1:MAIT TCR axis has not been studied in detail.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	Frontiers Media
ISSN:	1664-3224
Funders:	MRC
Date of First Compliant Deposit:	21 February 2023
Date of Acceptance:	25 January 2023
Last Modified:	09 May 2023 16:31
URI:	https://orca.cardiff.ac.uk/id/eprint/157101

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