A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells

• Published in: The Journal of experimental medicine Vol. 211; no. 8; pp. 1585 - 1600
• Main Authors: Eckle, Sidonia B G, Birkinshaw, Richard W, Kostenko, Lyudmila, Corbett, Alexandra J, McWilliam, Hamish E G, Reantragoon, Rangsima, Chen, Zhenjun, Gherardin, Nicholas A, Beddoe, Travis, Liu, Ligong, Patel, Onisha, Meehan, Bronwyn, Fairlie, David P, Villadangos, Jose A, Godfrey, Dale I, Kjer-Nielsen, Lars, McCluskey, James, Rossjohn, Jamie
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 28.07.2014
• Subjects: Antigens - metabolism; Antigens, Differentiation, B-Lymphocyte - metabolism; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - metabolism; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - metabolism; Histocompatibility Antigens Class II - metabolism; Humans; Ligands; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Minor Histocompatibility Antigens; Models, Molecular; Mucous Membrane - cytology; Mucous Membrane - immunology; Protein Binding - drug effects; Protein Stability - drug effects; Pterins - chemistry; Pterins - pharmacology; Receptors, Antigen, T-Cell - metabolism; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Staining and Labeling; Surface Plasmon Resonance; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Up-Regulation - drug effects
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20140484

Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) α-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR β-chains. MAIT TCRs can bind folate- and riboflavin-based metabolites restricted by the major histocompatibility complex (MHC)-related class I-like molecule, MR1. However, the impact of MAIT TCR and MR1-ligand heterogeneity on MAIT cell biology is unclear. We show how a previously uncharacterized MR1 ligand, acetyl-6-formylpterin (Ac-6-FP), markedly stabilized MR1, potently up-regulated MR1 cell surface expression, and inhibited MAIT cell activation. These enhanced properties of Ac-6-FP were attributable to structural alterations in MR1 that subsequently affected MAIT TCR recognition via conformational changes within the complementarity-determining region (CDR) 3β loop. Analysis of seven TRBV6-1(+) MAIT TCRs demonstrated how CDR3β hypervariability impacted on MAIT TCR recognition by altering TCR flexibility and contacts with MR1 and the Ag itself. Ternary structures of TRBV6-1, TRBV6-4, and TRBV20(+) MAIT TCRs in complex with MR1 bound to a potent riboflavin-based antigen (Ag) showed how variations in TRBV gene usage exclusively impacted on MR1 contacts within a consensus MAIT TCR-MR1 footprint. Moreover, differential TRAJ gene usage was readily accommodated within a conserved MAIT TCR-MR1-Ag docking mode. Collectively, MAIT TCR heterogeneity can fine-tune MR1 recognition in an Ag-dependent manner, thereby modulating MAIT cell recognition.