MAIT cells and MR1-antigen recognition

https://doi.org/10.1016/j.coi.2017.04.002Get rights and content

Highlights

  • MR1 presents vitamin B precursors and metabolites to MAIT cells.

  • The MR1-restricted T cell repertoire is diverse.

  • MAIT TCR heterogeneity can impact on MR1-antigen responsiveness.

  • MR1 presents drugs and drug-like molecules.

Mucosal-associated invariant T cells (MAIT cells) are innate-like T cells that recognise antigens presented by the monomorphic MHC-I related molecule, MR1. Distinct from the conventional MHC-restricted T cell system, MR1 presents small-molecule precursors, derived from microbial biosynthesis of riboflavin, to activate the innate MAIT cell effector potential. Recent data demonstrates how: vitamin B precursors modulate intracellular trafficking of MR1 and impact on MAIT cell development; variation in the MAIT cell antigen receptor sequence impacts MR1-antigen recognition; and most notably, how MR1 can capture chemical identities distinct from riboflavin precursors, including drugs and drug-like molecules. With mounting evidence demonstrating their roles in immunity and pathology, understanding the MAIT-MR1-antigen axis may have profound implications for human diseases.

Introduction

T cells are central players in adaptive immunity that upon activation have the capacity to coordinate formidable and widespread immunological responses. Directing this activity is a highly specific intercellular system centred around the interaction between a surface-expressed heterodimeric antigen receptor on the T cell (the αβT cell receptor; TCR), which surveys the surface of antigen presenting cells for major histocompatibility complex (MHC) molecules presenting peptide epitopes [1]. The highly polymorphic nature of these MHC molecules is a central feature in immunological genetic diversity. Increasingly recognised however, are populations of ‘unconventional’ T cells, which are dependent on monomorphic MHC-I-like molecules presenting non-peptide antigens. Namely, CD1 and MR1 present lipid-based and vitamin B-based antigens for T cell surveillance. Along with the specific responses of the T cells that recognise CD1 and MR1, these antigen-presenting molecules are generating great interest within the field, from a fundamental and applied aspect [2, 3]. This review will focus on recent advances in the function of mucosal-associated invariant T cells (MAIT cells) that recognise vitamin B-related molecules presented by MR1.

Section snippets

MAIT cells

Initially named after being observed as present in the intestinal lamina propria, MAIT cells are a highly abundant T cell subset in humans [4]. They comprise up to 10% of T cells in peripheral blood of adults and up to 45% of T cells in the liver [5, 6]. Initially identified whilst investigating CD4CD8 T cell populations, it is now accepted that they are predominantly CD8αα+ in human, mouse and macaque, although the contribution of the CD8 co-receptor on MAIT cell functionality remains

Biosynthetic vitamin B products as determinants of bacterial infection

MR1 is ubiquitously expressed in all cells (but at very low levels on the cell surface as judged by anti-MR1 staining) and, contrary to its name, it does not present peptide antigens nor traffics similarly to MHC-I molecules. The nature of the MR1 antigen remained unknown long after the first description of MAIT cells [4, 9]. The seminal observation that MAIT cells exhibited reactivity to bacterial pathogens that synthesised riboflavin was crucial in determining that MR1 presents precursors of

Structural determinants of vitamin B-related recognition.

The small, unstable antigens presented by MR1 not only require a unique means of capture, but their recognition by the MAIT TCR also necessitates a sensitive and finely tuned mechanism. Indeed, an antigenic pyrimidine is recognised by a single direct contact point between the ribityl moiety of the ligand and a tyrosine residue at position 95 (Y95α) in the CDR3α loop of the MAIT TCR (Figure 3b and d) [18••, 29]. Accordingly, the semi-invariant TCR usage facilitates a consistent docking mode,

MR1 captures drugs and drug-like molecules

The topological differences between the riboflavin-derived and folate-derived antigens are noteworthy and with such apparent plasticity of the MR1 binding groove, it was speculated that MR1 could bind a range of ligands that possessed such scaffolds. Indeed, Keller et al. [33••] recently used in silico docking techniques to identify a large panel of potential MR1 bound small molecules, which were then validated functionally. With a particular focus on drugs and drug-like molecules, these new

MAIT cell activation and disease

While MAIT cell activation to microbial infection is dependent on MR1 recognition, MAIT cell activity in vivo requires more than this MAIT TCR–MR1-antigen interaction. Specifically, administration of synthetic 5-OP-RU alone causes CD69 upregulation on MAIT cells, but does not result in MAIT cell proliferation in the lungs [36]. 5-OP-RU plus additional TLR-agonists, however, causes higher levels of activation as well as proliferation of the MAIT cell pool [36]. The full range of signals capable

Conclusions

Since the initial identification of MR1-restricted ligands, significant progress has been made in understanding fundamental aspects of the MAIT TCR–MR1 axis. With greater understanding of MAIT cell function, improved description of the cell phenotype and identification afforded with the use of MR1-tetramers [10•, 18••], the role of MAIT cells in diseases will no doubt be elucidated allowing their potential as a therapeutic target to be explored.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants from the Australian Research Council and the National Health and Medical Research Council of Australia. AJC is an ARC Future Fellow, and JR is an ARC Laureate Fellow. We would like to thank Vanette Tran for help with illustrations.

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