Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor. 2021

Michael T Rice, and Anouk von Borstel, and Priyanka Chevour, and Wael Awad, and Lauren J Howson, and Dene R Littler, and Nicholas A Gherardin, and Jérôme Le Nours, and Edward M Giles, and Richard Berry, and Dale I Godfrey, and Martin S Davey, and Jamie Rossjohn, and Benjamin S Gully
Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Unlike conventional αβ T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1+ and Vδ2+ γδ TCR-mediated ligand recognition, the mode of Vδ3+ TCR ligand engagement is unknown. MHC class I-related protein, MR1, presents vitamin B metabolites to αβ T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2- γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3+ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3+ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008297 Male Males
D011948 Receptors, Antigen, T-Cell Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (CD3 COMPLEX). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains. Antigen Receptors, T-Cell,T-Cell Receptors,Receptors, T-Cell Antigen,T-Cell Antigen Receptor,T-Cell Receptor,Antigen Receptor, T-Cell,Antigen Receptors, T Cell,Receptor, T-Cell,Receptor, T-Cell Antigen,Receptors, T Cell Antigen,Receptors, T-Cell,T Cell Antigen Receptor,T Cell Receptor,T Cell Receptors,T-Cell Antigen Receptors
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072336 Mucosal-Associated Invariant T Cells A subset of T-lymphocytes that are present in large numbers at MUCOUS MEMBRANES and respond to INFECTIONS. They express a conserved invariant T-CELL RECEPTOR ALPHA-CHAIN that enables them to respond to infections by sensing RIBOFLAVIN metabolites of pathogens. MAIT Cell,Mucosal-Associated Invariant T Cell,MAIT Cells,Cell, MAIT,Cells, MAIT,Mucosal Associated Invariant T Cell,Mucosal Associated Invariant T Cells
D000075942 Intraepithelial Lymphocytes T Lymphocytes with limited diversity of receptors (e.g., ALPHA E INTEGRINS) in the epidermis of the skin and the mucosal linings. They recognize common microbes via T-CELL RECEPTORS and PATHOGEN-ASSOCIATED MOLECULAR PATTERN MOLECULES and function as effector cells for INNATE IMMUNITY. Activation of intraepithelial lymphocytes is a marker for various gastrointestinal diseases (e.g., CELIAC DISEASE; HAIRY CELL LEUKEMIA; and ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA). Dendritic Epithelial T Cell,Gamma Delta T Cell,Gamma Delta T Lymphocyte,Intraepithelial Lymphocyte,Intraepithelial T Cell,Intraepithelial T Lymphocyte,Mucosal T Cell,Mucosal T Lymphocyte,Dendritic Epithelial T Cells,Gamma Delta T Cells,Gamma Delta T Lymphocytes,Intraepithelial T Cells,Intraepithelial T Lymphocytes,Mucosal T Cells,Mucosal T Lymphocytes,Lymphocyte, Intraepithelial,Lymphocytes, Intraepithelial,T Cell, Intraepithelial,T Cell, Mucosal,T Cells, Intraepithelial,T Cells, Mucosal,T Lymphocyte, Intraepithelial,T Lymphocyte, Mucosal,T Lymphocytes, Intraepithelial,T Lymphocytes, Mucosal
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D015395 Histocompatibility Antigens Class I Membrane glycoproteins consisting of an alpha subunit and a BETA 2-MICROGLOBULIN beta subunit. In humans, highly polymorphic genes on CHROMOSOME 6 encode the alpha subunits of class I antigens and play an important role in determining the serological specificity of the surface antigen. Class I antigens are found on most nucleated cells and are generally detected by their reactivity with alloantisera. These antigens are recognized during GRAFT REJECTION and restrict cell-mediated lysis of virus-infected cells. Class I Antigen,Class I Antigens,Class I Histocompatibility Antigen,Class I MHC Protein,Class I Major Histocompatibility Antigen,MHC Class I Molecule,MHC-I Peptide,Class I Histocompatibility Antigens,Class I Human Antigens,Class I MHC Proteins,Class I Major Histocompatibility Antigens,Class I Major Histocompatibility Molecules,Human Class I Antigens,MHC Class I Molecules,MHC-I Molecules,MHC-I Peptides,Antigen, Class I,Antigens, Class I,I Antigen, Class,MHC I Molecules,MHC I Peptide,MHC I Peptides,Molecules, MHC-I,Peptide, MHC-I,Peptides, MHC-I
D015778 Minor Histocompatibility Antigens Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. Histocompatibility Antigens, Minor,Minor Histocompatibility Antigen,Minor Histocompatibility Peptide,Minor Histocompatibility Peptides,Antigen, Minor Histocompatibility,Histocompatibility Antigen, Minor,Histocompatibility Peptide, Minor,Histocompatibility Peptides, Minor,Peptide, Minor Histocompatibility

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