Biochemistry and Pharmacology - Research Publications

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Author: Godfrey, Dale × End date: 2019 × Start date: 2010 × Type: Journal Article ×

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    A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
    Eckle, SBG ; Birkinshaw, RW ; Kostenko, L ; Corbett, AJ ; McWilliam, HEG ; Reantragoon, R ; Chen, Z ; Gherardin, NA ; Beddoe, T ; Liu, L ; Patel, O ; Meehan, B ; Fairlie, DP ; Villadangos, JA ; Godfrey, DI ; Kjer-Nielsen, L ; McCluskey, J ; Rossjohn, J (ROCKEFELLER UNIV PRESS, 2014-07-28)
    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.