1. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
- Author
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Jose A Villadangos, Dale I. Godfrey, Lars Kjer-Nielsen, Sidonia B G Eckle, Lyudmila Kostenko, James McCluskey, Richard W Birkinshaw, Ligong Liu, Hamish E G McWilliam, Jamie Rossjohn, Alexandra J. Corbett, Rangsima Reantragoon, Travis Clarke Beddoe, Bronwyn S. Meehan, Zhenjun Chen, Nicholas A Gherardin, Onisha Patel, and David P. Fairlie
- Subjects
T-Lymphocytes ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Complementarity determining region ,Mucosal associated invariant T cell ,Biology ,Major histocompatibility complex ,Article ,Minor Histocompatibility Antigens ,Antigen ,Minor histocompatibility antigen ,medicine ,Humans ,Immunology and Allergy ,Mucous Membrane ,Bacteria ,Histocompatibility Antigens Class I ,T-cell receptor ,Histocompatibility Antigens Class II ,hemic and immune systems ,Molecular biology ,Antigens, Differentiation, B-Lymphocyte ,medicine.anatomical_structure ,biology.protein ,Cell activation - Abstract
A novel MAIT cell antagonist, Ac-6-FP, stabilizes MR1 and can inhibit MAIT cell activation with the flexible TCR β-chain serving to fine-tune the affinity of the TCR for antigen-MR1 complexes., 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.
- Published
- 2014