A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. Academic Article uri icon

abstract

  • 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.

authors

  • 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

publication date

  • 2014

has subject area