Diversity of T Cells Restricted by the MHC Class I-Related Molecule MR1 Facilitates Differential Antigen Recognition

Abstract

A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2(+) MAIT cells. This recognition was attributable to CDR3β loop-mediated effects within a consensus TRAV1-2(+) TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a diverse population of "atypical" TRAV1-2(-) MR1-restricted T cells. We have shown that TRAV1-2(-) T cells are phenotypically heterogeneous and largely distinct from TRAV1-2(+) MAIT cells. A TRAV1-2(-) TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1-2(+) TCR. Accordingly, diversity within the MR1-restricted T cell repertoire leads to differing MR1-restricted Ag specificity.

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells

“…Notably, while 3-F-SA was non-stimulatory against the MAIT TCRs tested, 5-F-SA could weakly activate a MAIT TCR expressing cell line, indicating that subtle structural changes in the ligand, coupled with MAIT TCR heterogeneity, may lead to unanticipated MAIT cell activation. This resonates with the recent finding that diversity in the MAIT TCR repertoire can permit some folic acid derivatives to stimulate some MR1-restricted T cells and MAIT cells 22 .…”

“…While the degree to which methotrexate and aminopterin degrade to 2,4-DA-6-FP in patients is unclear, high dose chemotherapeutic administration of methotrexate can result in much higher plasma concentrations of the drug than what is required to upregulate MR1 26 . In addition, we speculate that MR1 tetramers loaded with 2,4-DA-6-FP may bind some MAIT cells, consistent with the presence of some MR1 reactive T-cells recognising 6-FP 22 . Thus, patients administered with continual low-dose methotrexate during their treatment for rheumatoid arthritis, 27 other autoimmune diseases and cancers, are also continually exposed to low levels of 2,4-DA-6-FP.…”

“…The mode of binding of DCF within the MR1 cleft was distinct from that of other MR1 bound ligands, not forming a Schiff base with Lys43, as also observed for some ribityllumazines 17 . Crucially, the 5-OH-DCF metabolite directly contacted the MAIT TCR  and -chains, which provided insight into both its antigenicity and the ability of various DCF metabolites to activate specific MAIT TCRs 22 , suggesting MAIT cell subset specific activation by DCF metabolites.…”

“…All cells were cultured in RPMI medium supplemented with 10 % fetal calf serum and serum complement were generated based on TCR sequences described previously 22 . For the generation of high-level MR1…”

Donor-unrestricted T cells in the human CD1 system

“…However, MAIT cells with TRAJ20 or TRAJ12 are now described (Patel et al 2013; Reantragoon et al 2013). A recent study shows that MR1-reactive T cells can express TCRs not encoded by TRAV1-2, which is an immunogenetic feature previously thought to be essential for MR1 recognition (Gherardin et al 2016). Also, NKT cells expressing the atypical V gene, TRAV13, can bind to CD1d-α-galactosyl ceramide (Uldrich et al 2011).…”