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
Affiliations
Brian P. McSharry
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia; School of Microbiology, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland
Carolyn Samer
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Hamish E.G. McWilliam
Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
Caroline L. Ashley
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Michael B. Yee
Departments of Ophthalmology and of Molecular Microbiology and Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
Megan Steain
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Ligong Liu
ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
David P. Fairlie
ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Paul R. Kinchington
Departments of Ophthalmology and of Molecular Microbiology and Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA
James McCluskey
Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia
Allison Abendroth
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Jose A. Villadangos
Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute of Infection and Immunity, Melbourne, VIC, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
Jamie Rossjohn
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Wales, UK
Barry Slobedman
Discipline of Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia; Corresponding author
Summary: 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. : The antigen-presenting molecule MR1 presents bacterial and fungal metabolites to MAIT cells. McSharry et al. show that the herpesviruses HSV-1 and CMV disrupt MR1 expression. Downregulation of MR1 by HSV-1 inhibits bacterially driven MAIT TCR-dependent activation. This provides evidence of virus immunomodulatory control of the MR1-restricted immune response. Keywords: herpesvirus, herpes simplex virus, cytomegalovirus, MR1, MAIT cell, immune evasion, virus targeting of MHC I-like molecules
