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Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation.
Ashley, Caroline L; McSharry, Brian P; McWilliam, Hamish E G; Stanton, Richard J; Fielding, Ceri A; Mathias, Rommel A; Fairlie, David P; McCluskey, James; Villadangos, Jose A; Rossjohn, Jamie; Abendroth, Allison; Slobedman, Barry.
Afiliación
  • Ashley CL; Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
  • McSharry BP; Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
  • McWilliam HEG; School of Dentistry and Medical Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia.
  • Stanton RJ; Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
  • Fielding CA; Department of Biochemistry and Pharmacology, Institute of Molecular Science and Biotechnology (Bio21), The University of Melbourne, Melbourne, VIC, Australia.
  • Mathias RA; Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
  • Fairlie DP; Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
  • McCluskey J; Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
  • Villadangos JA; Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
  • Rossjohn J; ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
  • Abendroth A; Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
  • Slobedman B; Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
Front Immunol ; 14: 1107497, 2023.
Article en En | MEDLINE | ID: mdl-36845106
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células T Invariantes Asociadas a Mucosa Límite: Humans Idioma: En Revista: Front Immunol Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células T Invariantes Asociadas a Mucosa Límite: Humans Idioma: En Revista: Front Immunol Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza