Download MendeleyA molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells.
Eckle, S.B., Birkinshaw, R.W., Kostenko, L., Corbett, A.J., McWilliam, H.E., Reantragoon, R., Chen, Z., Gherardin, N.A., Beddoe, T., Liu, L., Patel, O., Meehan, B., Fairlie, D.P., Villadangos, J.A., Godfrey, D.I., Kjer-Nielsen, L., McCluskey, J., Rossjohn, J.(2014) J Exp Med 211: 1585-1600
- PubMed: 25049336
- DOI: https://doi.org/10.1084/jem.20140484
- Primary Citation of Related Structures:
4PJ5, 4PJ7, 4PJ8, 4PJ9, 4PJA, 4PJB, 4PJC, 4PJD, 4PJE, 4PJF, 4PJG, 4PJH, 4PJI, 4PJX - PubMed Abstract:
Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) ¦Á-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR ¦Â-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) 3¦Â loop. Analysis of seven TRBV6-1(+) MAIT TCRs demonstrated how CDR3¦Â 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.
Organizational Affiliation:
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
