TY - JOUR
T1 - A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
AU - Eckle, Sidonia B G
AU - Birkinshaw, Richard W
AU - Kostenko, Lyudmila
AU - Corbett, Alexandra J
AU - McWilliam, Hamish E G
AU - Reantragoon, Rangsima
AU - Chen, Zhenjun
AU - Gherardin, Nicholas A
AU - Beddoe, Travis C
AU - Liu, Ligong
AU - Patel, Onisha
AU - Meehan, Bronwyn
AU - Fairlie, David P
AU - Villadangos, Jose A
AU - Godfrey, Dale I
AU - Kjer-Nielsen, Lars
AU - McCluskey, James
AU - Rossjohn, Jamie
PY - 2014
Y1 - 2014
N2 - Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) alpha-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR beta-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) 3beta loop. Analysis of seven TRBV6-1(+) MAIT TCRs demonstrated how CDR3beta 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.
AB - Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) alpha-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR beta-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) 3beta loop. Analysis of seven TRBV6-1(+) MAIT TCRs demonstrated how CDR3beta 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.
UR - http://jem.rupress.org/content/211/8/1585.full.pdf+html
U2 - 10.1084/jem.20140484
DO - 10.1084/jem.20140484
M3 - Article
SN - 0022-1007
VL - 211
SP - 1585
EP - 1600
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
ER -