MAIT cells and MR1-antigen recognition
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 CD4−CD8− 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.
References (60)
Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells
Blood
(2011)Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress
Mucosal Immunol.
(2013)High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells
Immunology
(2015)MR1 presents microbial vitamin B metabolites to MAIT cells
Nature
(2012)Endosomal MR1 trafficking plays a key role in presentation of Mycobacterium tuberculosis ligands to MAIT cells
PLoS Pathog.
(2016)Immune self-reactivity triggered by drug-modified HLA-peptide repertoire
Nature
(2012)Specific MAIT cell behaviour among innate-like T lymphocytes in critically ill patients with severe infections
Intensive Care Med.
(2014)Human mucosa-associated invariant T cells accumulate in colon adenocarcinomas but produce reduced amounts of IFN-gamma
J. Immunol.
(2015)Mucosal-associated invariant T cell deficiency in systemic lupus erythematosus
J. Immunol.
(2014)Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients
J. Clin. Invest.
(2015)
T cell antigen receptor recognition of antigen-presenting molecules
Annu. Rev. Immunol.
Lipid and small-molecule display by CD1 and MR1
Nat. Rev. Immunol.
The burgeoning family of unconventional T cells
Nat. Immunol.
Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1
Nature
IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells
J. Immunol.
Enhanced Th1/Th17 functions of CD161+ CD8+ T Cells in mucosal tissues of rhesus macaques
PLoS One
Human mucosal associated invariant T cells detect bacterially infected cells
PLoS Biol.
Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells
J. Exp. Med.
Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers
J. Exp. Med.
A gene outside the human MHC related to classical HLA class I genes
Science
The IL-17A-producing CD8+ T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells
J. Invest. Dermatol.
Stepwise development of MAIT cells in mouse and human
PLoS Biol.
Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain
J. Exp. Med.
An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals
J. Exp. Med.
T-cell activation by transitory neo-antigens derived from distinct microbial pathways
Nature
CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner
Eur. J. Immunol.
Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation
Proc. Natl. Acad. Sci. U. S. A.
MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets
Mucosal Immunol.
A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
Nat. Immunol.
Recognition of vitamin B precursors and byproducts by mucosal associated invariant T cells
J. Biol. Chem.
Cited by (61)
The MR1/MAIT cell axis in CNS diseases
2024, Brain, Behavior, and ImmunityT Cell Repertoire Homogeneity and Blood-Gut Overlap in Patients With Inflammatory Bowel Disease
2024, Cellular and Molecular Gastroenterology and HepatologyNew insights into MAIT cells in autoimmune diseases
2023, Biomedicine and PharmacotherapyUnconventional MAIT cell responses to bacterial infections
2022, Seminars in Immunology