Recognition of vitamin B metabolites by mucosal-associated invariant T cells

Abstract

The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR a-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures.

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

“…We did not find amino acid motifs within the CDR3b, although it does contact the MR1-a1 chain 31,32 . The absence of conserved motifs is consistent with the known absence of effects on antigen reactivity on single amino acid substitutions in the CDR3b chain of MAIT TCR 30,46 .…”

“…The co-crystal of the TCR of MAIT cells and MR1 showed that CDR3b residues form van der Waals interactions with the MR1 a1 helix, thereby contributing to the overall interaction between the two proteins 31,32 . The preferential length of MAIT CDR3b sequences might contribute to optimal recognition of MR1-antigen complexes.…”

Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection

“…The remarkable evolutionary conservation of this system (25) implies an essential role in host defense, which has yet to be defined. It has recently been shown that MAIT cells recognize small molecule derivatives of highly conserved biosynthetic pathways of riboflavin and folic acid metabolism in bacteria, mycobacteria, and yeasts (26,27) presented on the nonpolymorphic class 1b antigen presenting molecule major histocompatibility complex (MHC)-related protein 1 (MR1) (28,29). Because of their propensity for intracellular invasion of epithelia and macrophages (6), and because they express this riboflavin pathway (30), NTHi is a likely target of MAIT-cell immunity.…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…Recent work conducted by Ló pez-Sagaseta et al [67] and Patel et al [68] revealed interesting structural, biophysical and biochemical aspects of ligand binding to MR1 and recognition of this complex by MAIT cells. Furthermore, the studies reveal how MAIT cells exert their effector functions via CDR3b loop diversity and alternate Vb gene usage.…”