Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation.
MAIT cells
MHC class I related protein-1
MR1
herpesvirus
human cytomegalovirus
immune modulation
mucosal-associated invariant T cells
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
25
11
2022
accepted:
25
01
2023
entrez:
27
2
2023
pubmed:
28
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
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). 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. 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. 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.
Identifiants
pubmed: 36845106
doi: 10.3389/fimmu.2023.1107497
pmc: PMC9950634
doi:
Substances chimiques
Histocompatibility Antigens Class I
0
Minor Histocompatibility Antigens
0
Receptors, Antigen, T-Cell
0
MR1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1107497Subventions
Organisme : HCRW_
ID : HCRW_HS-20-30
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S00971X/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI148407
Pays : United States
Informations de copyright
Copyright © 2023 Ashley, McSharry, McWilliam, Stanton, Fielding, Mathias, Fairlie, McCluskey, Villadangos, Rossjohn, Abendroth and Slobedman.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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