Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717-723

Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Nature (Impact Factor: 41.46). 10/2012; 491(7426). DOI: 10.1038/nature11605
Source: PubMed


Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.

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    • "They express a highly restricted T cell receptor (TCR) repertoire composed in humans of a single invariant Vα24Jα18 and Vα7.2Jα33 for iNKT and MAIT cells, respectively. In contrast to conventional T cells that recognize peptides, iNKT cells recognize glycolipids presented by CD1d while MAIT cells are activated by vitamin B metabolites presented by the MHC-related protein 1 (MR1) molecules [13], [14]. Both iNKT and MAIT cells are generally regarded as protective against infections and we reported that iNKT cells also attenuated the development of anti-glomerular basement membrane glomerulonephritis in a murine model [15], [16], [17], [18]. "
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    ABSTRACT: Clinicians are well aware of existing pharmacologically-induced immune deficient status in kidney-transplanted patients that will favor their susceptibility to bacterial or viral infections. Previous studies indicated that advanced Stage 4-5 Chronic Kidney Disease might also be regarded as an immune deficiency-like status as well, even though the mechanisms are not fully understood. Here, we analyzed the ex vivo frequency and the functional properties of both conventional and innate-like T (ILT) lymphocyte subsets in the peripheral blood of 35 patients on hemodialysis, 29 kidney transplanted patients and 38 healthy donors. We found that peripheral blood cell count of ILT cells, as iNKT (invariant Natural Killer T) and MAIT (mucosal-associated invariant T), were significantly decreased in hemodialyzed patients compared to healthy controls. This deficiency was also observed regarding conventional T cells, including the IL-17-producing CD4+ Th17 cells. Pertaining to regulatory T cells, we also noticed major modifications in the global frequency of CD4+CD25+Foxp3+ T lymphocytes, including the resting suppressive CD45RA+Foxp3lo and activated suppressive CD45RA-Foxp3hi T cell subpopulations. We found no significant differences between the immune status of hemodialyzed and kidney-transplanted subjects. In conclusion, we demonstrated that both ILT and conventional T cell numbers are equally impaired in hemodialyzed and kidney-transplanted patients.
    PLoS ONE 08/2014; 9(8):e105422. DOI:10.1371/journal.pone.0105422 · 3.23 Impact Factor
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    • "Although the MR1 transcript is expressed widely (Hashimoto et al., 1995; Riegert et al., 1998), cell surface expression of MR1 is very low/absent, thereby indicating that other factors, including Ag supply, can determine the level of MR1 that egresses to the cell membrane (Huang et al., 2008; Chua et al., 2011). Recently, it has been established that MR1 can bind vitamin B–based precursors and derivatives that originate from folic acid (vitamin B9) and riboflavin (vitamin B2) biosynthesis (Kjer-Nielsen et al., 2012). Specifically, MR1 can present 6-formylpterin (6-FP), a naturally occurring photo-degradation product of folic acid, and a series of ribityllumazines, including 6,7-dimethyl-8-d-ribityllumazine (RL-6,7-DiMe), 6-methyl- 7-hydroxy-8-d-ribityllumazine (RL-6-Me-7-OH; Kjer-Nielsen et al., 2012; Patel et al., 2013), 5-(2-oxoethylideneamino)-6-d- ribitylaminouracil (5-OE-RU), and 5-(2-oxopropylideneamino) -6-d-ribitylaminouracil (5-OP-RU; Corbett et al., 2014). "
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    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.
    Journal of Experimental Medicine 07/2014; 211(8). DOI:10.1084/jem.20140484 · 12.52 Impact Factor
    • "MR1 is ubiquitously present in all cell types and its conservation suggests an important evolutionary conserved role in immunobiology108109. Though MR1 shares sequence and structural similarity with the antigen-presenting molecules encoded by MHC-I and CD1 gene families, the structure of its antigen-binding groove is distinct from that of MHC-I and CD1 molecules110. The MR1 antigen-binding groove is made of charged and hydrophobic amino acid residues, with a clear deep pocket that has a small portal, probably used by bound antigens to protrude outside the pocket. "
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    ABSTRACT: The immune system has evolved to recognize a wide range of antigenic molecules of self and non-self origin. The stimulatory antigens form complexes with antigen-presenting molecules and directly interact with the T cell receptor (TCR). Peptidic antigens associate with major histocompatibility complex (MHC) molecules and therefore, are indicated as MHC-restricted. Non-peptidic antigens do not bind to MHC molecules and are presented by other classes of antigen-presenting molecules. These non-MHC restricted antigens include glycolipid molecules, phosphorylated metabolites of the mevalonate pathway and vitamin B2 precursors. T cells specific for non-peptidic antigens have important roles in host defense against infections, autoimmunity, allergies and tumour immunosurveillance. Hence, understanding the molecular interactions between the antigen presenting cell (APC) and the T cells with non-peptidic specificity is of great relevance. Here, we review current knowledge of this type of T cells, their TCR repertoire, the structural aspects of recognized antigens, the mode of antigen recognition, and their function with special emphasis on their role in infectious diseases.
    The Indian Journal of Medical Research 11/2013; 138(5):620-31. · 1.40 Impact Factor
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