Highlights d The herpesviruses HSV-1 and CMV suppress the antigen presentation molecule MR1 d HSV-1 targets immature MR1 for degradation although mature MR1 remains protected d The Us3 protein of HSV-1 is partially responsible for suppression of MR1 d Suppression of MR1 by HSV-1 inhibits MAIT TCR-dependent activation 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 MR1restricted immune response.
SUMMARYThe 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 presentation molecule MR1 presents ligands derived from the riboflavin (vitamin B) synthesis pathway, which is not present in mammalian species or viruses, to Mucosal Associated Invariant T (MAIT) cells. In this study, we demonstrate that Varicella Zoster Virus (VZV) profoundly suppresses MR1 expression. We show that VZV targets the intracellular reservoir of immature MR1 for degradation, whilst pre-existing, ligand bound cell surface MR1 is protected from such targeting; thereby highlighting an intricate temporal relationship between infection and ligand availability. We also identify VZV open reading frame (ORF) 66 as functioning to suppress MR1 expression when this viral protein is expressed during transient transfection, but this is not apparent during infection with a VZV mutant virus lacking ORF66 expression. This indicates that VZV is likely to encode multiple viral genes that target MR1. Overall, we identify an immunomodulatory function of VZV whereby infection suppresses the MR1 biosynthesis pathway.
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