Virus-mediated suppression of the antigen presentation molecule MR1

Brian P McSharry; Carolyn Samer; Hamish E G McWilliam; Caroline L Ashley; Michael B Yee; Megan Steain; Ligong Liu; David P Fairlie; Paul R Kinchington; James McCluskey; Allison Abendroth; Jose A Villadangos; Jamie Rossjohn; Barry Slobedman

doi:10.1016/j.celrep.2020.02.017

Virus-mediated suppression of the antigen presentation molecule MR1

Brian P McSharry, Carolyn Samer, Hamish E G McWilliam, Caroline L Ashley, Michael B Yee, Megan Steain, Ligong Liu, David P Fairlie, Paul R Kinchington, James McCluskey, Allison Abendroth, Jose A Villadangos, Jamie Rossjohn, Barry Slobedman

Dentistry and Medical Sciences

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

40 Downloads (Pure)

Abstract

The antigen-presenting molecule MR1 presents microbial metabolites related to vitamin B2 biosynthesis to mucosal-associated invariant T cells (MAIT cells). Although bacteria and fungi drive the MR1 biosynthesis pathway, viruses have not previously been implicated in MR1 expression or its antigen presentation. We demonstrate that several herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1). This virus profoundly suppresses MR1 cell surface expression and targets the molecule for proteasomal degradation, whereas ligand-induced cell surface expression of MR1 prior to infection enables MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 is dependent on de novo viral gene expression, and we identify the Us3 viral gene product as functioning to target MR1. Furthermore, HSV-1 downregulation of MR1 disrupts MAIT T cell receptor (TCR) activation. Accordingly, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT TCR axis.

Original language	English
Article number	e4
Pages (from-to)	2948-2962
Number of pages	20
Journal	Cell Reports
Volume	30
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.02.017
Publication status	Published - 03 Mar 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2020.02.017Licence: CC BY-NC-ND

166385398 published articleFinal published version, 2.76 MBLicence: CC BY-NC-ND

Cite this

McSharry, B. P., Samer, C., McWilliam, H. E. G., Ashley, C. L., Yee, M. B., Steain, M., Liu, L., Fairlie, D. P., Kinchington, P. R., McCluskey, J., Abendroth, A., Villadangos, J. A., Rossjohn, J., & Slobedman, B. (2020). Virus-mediated suppression of the antigen presentation molecule MR1. Cell Reports, 30(9), 2948-2962. Article e4. https://doi.org/10.1016/j.celrep.2020.02.017

@article{ec9d2e96a29746308d74c53e1a0efa29,

title = "Virus-mediated suppression of the antigen presentation molecule MR1",

abstract = "The antigen-presenting molecule MR1 presents microbial metabolites related to vitamin B2 biosynthesis to mucosal-associated invariant T cells (MAIT cells). Although bacteria and fungi drive the MR1 biosynthesis pathway, viruses have not previously been implicated in MR1 expression or its antigen presentation. We demonstrate that several herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1). This virus profoundly suppresses MR1 cell surface expression and targets the molecule for proteasomal degradation, whereas ligand-induced cell surface expression of MR1 prior to infection enables MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 is dependent on de novo viral gene expression, and we identify the Us3 viral gene product as functioning to target MR1. Furthermore, HSV-1 downregulation of MR1 disrupts MAIT T cell receptor (TCR) activation. Accordingly, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT TCR axis.",

keywords = "Antigen Presentation/immunology, Cell Line, Cell Membrane/metabolism, Cytomegalovirus/physiology, Female, Fibroblasts/metabolism, Gene Expression Regulation, Viral/drug effects, Herpesvirus 1, Human/physiology, Histocompatibility Antigens Class I/metabolism, Humans, Jurkat Cells, Ligands, Male, Minor Histocompatibility Antigens/metabolism, Mucosal-Associated Invariant T Cells/immunology, Proteasome Inhibitors/pharmacology, Protein-Serine-Threonine Kinases/metabolism, Proteolysis/drug effects, Viral Proteins/metabolism, MR1, MAIT cell, Immune evasion, Virus targeting of MHC I-like molecules",

author = "McSharry, {Brian P} and Carolyn Samer and McWilliam, {Hamish E G} and Ashley, {Caroline L} and Yee, {Michael B} and Megan Steain and Ligong Liu and Fairlie, {David P} and Kinchington, {Paul R} and James McCluskey and Allison Abendroth and Villadangos, {Jose A} and Jamie Rossjohn and Barry Slobedman",

year = "2020",

month = mar,

day = "3",

doi = "10.1016/j.celrep.2020.02.017",

language = "English",

volume = "30",

pages = "2948--2962",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "9",

}

TY - JOUR

T1 - Virus-mediated suppression of the antigen presentation molecule MR1

AU - McSharry, Brian P

AU - Samer, Carolyn

AU - McWilliam, Hamish E G

AU - Ashley, Caroline L

AU - Yee, Michael B

AU - Steain, Megan

AU - Liu, Ligong

AU - Fairlie, David P

AU - Kinchington, Paul R

AU - McCluskey, James

AU - Abendroth, Allison

AU - Villadangos, Jose A

AU - Rossjohn, Jamie

AU - Slobedman, Barry

PY - 2020/3/3

Y1 - 2020/3/3

N2 - The antigen-presenting molecule MR1 presents microbial metabolites related to vitamin B2 biosynthesis to mucosal-associated invariant T cells (MAIT cells). Although bacteria and fungi drive the MR1 biosynthesis pathway, viruses have not previously been implicated in MR1 expression or its antigen presentation. We demonstrate that several herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1). This virus profoundly suppresses MR1 cell surface expression and targets the molecule for proteasomal degradation, whereas ligand-induced cell surface expression of MR1 prior to infection enables MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 is dependent on de novo viral gene expression, and we identify the Us3 viral gene product as functioning to target MR1. Furthermore, HSV-1 downregulation of MR1 disrupts MAIT T cell receptor (TCR) activation. Accordingly, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT TCR axis.

AB - The antigen-presenting molecule MR1 presents microbial metabolites related to vitamin B2 biosynthesis to mucosal-associated invariant T cells (MAIT cells). Although bacteria and fungi drive the MR1 biosynthesis pathway, viruses have not previously been implicated in MR1 expression or its antigen presentation. We demonstrate that several herpesviruses inhibit MR1 cell surface upregulation, including a potent inhibition by herpes simplex virus type 1 (HSV-1). This virus profoundly suppresses MR1 cell surface expression and targets the molecule for proteasomal degradation, whereas ligand-induced cell surface expression of MR1 prior to infection enables MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 is dependent on de novo viral gene expression, and we identify the Us3 viral gene product as functioning to target MR1. Furthermore, HSV-1 downregulation of MR1 disrupts MAIT T cell receptor (TCR) activation. Accordingly, virus-mediated targeting of MR1 defines an immunomodulatory strategy that functionally disrupts the MR1-MAIT TCR axis.

KW - Antigen Presentation/immunology

KW - Cell Line

KW - Cell Membrane/metabolism

KW - Cytomegalovirus/physiology

KW - Female

KW - Fibroblasts/metabolism

KW - Gene Expression Regulation, Viral/drug effects

KW - Herpesvirus 1, Human/physiology

KW - Histocompatibility Antigens Class I/metabolism

KW - Humans

KW - Jurkat Cells

KW - Ligands

KW - Male

KW - Minor Histocompatibility Antigens/metabolism

KW - Mucosal-Associated Invariant T Cells/immunology

KW - Proteasome Inhibitors/pharmacology

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Proteolysis/drug effects

KW - Viral Proteins/metabolism

KW - MR1

KW - MAIT cell

KW - Immune evasion

KW - Virus targeting of MHC I-like molecules

U2 - 10.1016/j.celrep.2020.02.017

DO - 10.1016/j.celrep.2020.02.017

M3 - Article

C2 - 32130899

SN - 2211-1247

VL - 30

SP - 2948

EP - 2962

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - e4

ER -

Virus-mediated suppression of the antigen presentation molecule MR1

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this