Biochemistry and Pharmacology - Research Publications

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Start date: 2020 × End date: 2020 × Author: Villadangos, Jose × Author: Rossjohn, Jamie ×

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    Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1
    Howson, LJ ; Awad, W ; von Borstel, A ; Lim, HJ ; McWilliam, HEG ; Sandoval-Romero, ML ; Majumdar, S ; Hamzeh, AR ; Andrews, TD ; McDermott, DH ; Murphy, PM ; Le Nours, J ; Mak, JYW ; Liu, L ; Fairlie, DP ; McCluskey, J ; Villadangos, JA ; Cook, MC ; Turner, SJ ; Davey, MS ; Ojaimi, S ; Rossjohn, J (American Association for the Advancement of Science, 2020-07-10)
    The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.
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    Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens
    McWilliam, HEG ; Mak, JYW ; Awad, W ; Zorkau, M ; Cruz-Gomez, S ; Lim, HJ ; Yan, Y ; Wormald, S ; Dagley, LF ; Eckle, SBG ; Corbett, AJ ; Liu, H ; Li, S ; Reddiex, SJJ ; Mintern, JD ; Liu, L ; McCluskey, J ; Rossjohn, J ; Fairlie, DP ; Villadangos, JA (NATL ACAD SCIENCES, 2020-10-06)
    The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.
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    Virus-Mediated Suppression of the Antigen Presentation Molecule MR1
    McSharry, BP ; Samer, C ; McWilliam, HEG ; Ashley, CL ; Yee, MB ; Steain, M ; Liu, L ; Fairlie, DP ; Kinchington, PR ; McCluskey, J ; Abendroth, A ; Villadangos, JA ; Rossjohn, J ; Slobedman, B (CELL PRESS, 2020-03-03)
    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.