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

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Eckle SB, Birkinshaw RW, Kostenko L, Corbett AJ, McWilliam HE, 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
OpenAccess logo J Exp Med 211 1585-600 (2014)
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Cited: 182 times
EuropePMC logo PMID: 25049336

Abstract

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.

Articles - 4pja mentioned but not cited (2)

  1. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. Eckle SB, Birkinshaw RW, Kostenko L, Corbett AJ, McWilliam HE, 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. J Exp Med 211 1585-1600 (2014)
  2. Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses. Chancellor A, Alan Simmons R, Khanolkar RC, Nosi V, Beshirova A, Berloffa G, Colombo R, Karuppiah V, Pentier JM, Tubb V, Ghadbane H, Suckling RJ, Page K, Crean RM, Vacchini A, De Gregorio C, Schaefer V, Constantin D, Gligoris T, Lloyd A, Hock M, Srikannathasan V, Robinson RA, Besra GS, van der Kamp MW, Mori L, Calogero R, Cole DK, De Libero G, Lepore M. J Exp Med 220 e20221939 (2023)


Reviews citing this publication (75)

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Articles citing this publication (105)

  1. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). 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