Journal Article

MR1 presents microbial vitamin B metabolites to MAIT cells

McConville, Malcolm J., Fairlie, David P., Williamson, Nicholas A., Patel, Onisha, Liu, Ligong, Khairallah, George N., Corbett, Alexandra J., McCluskey, James, Purcell, Anthony W., Kjer-Nielsen, Lars, Godfrey, Dale I., Meehan, Bronwyn, Reantragoon, Rangsima, Kostenko, Lyudmila, Le Nours, Jérôme, Bhati, Mugdha, Rossjohn, Jamie, Chen, Zhenjun, Dudek, Nadine L., O’Hair, Richard A. J.

2012

Overview

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. The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance. Immune surveillance role for MAIT cells Although mucosal-associated invariant T (MAIT) cells comprise up to 10% of the human T-cell population, surprisingly little is known about their role in physiology and pathology. This is in large part because the identity of the antigen or antigens recognized by MAIT cells in an MR1-restricted manner is unknown. This study reports the structure of the MHC-like molecule MR1 in complex with the vitamin B9-like protein pterin. Bacterial vitamin B derivatives are shown to activate MAIT cells, suggesting that the elusive antigens for MAIT cells are microbial vitamin metabolites and that the physiological role of these cells is to detect microbial infections.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/21/1293 / 631/250/254 / 631/45/535 / Acids / Antigen Presentation / Bacterial infections / Bacterial Infections - immunology / Bacterial Infections - microbiology / beta 2-Microglobulin - immunology / beta 2-Microglobulin - metabolism / Binding Sites / Biological and medical sciences / Cell culture / Cell Line / Chromatography / Crystallography, X-Ray / Folic acid / Folic Acid - chemistry / Folic Acid - immunology / Folic Acid - metabolism / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Health aspects / Histocompatibility Antigens - chemistry / Histocompatibility Antigens - immunology / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / Humanities and Social Sciences / Humans / Immunobiology / Immunologic Surveillance - immunology / Immunology / Infections / Jurkat Cells / Ligands / Lipids / Lymphocyte Activation / Mass spectrometry / Metabolites / Methods / Minor Histocompatibility Antigens / Models, Molecular / Modulation of the immune response (stimulation, suppression) / multidisciplinary / Photodegradation / Physiological aspects / Protein Refolding - drug effects / Pterins - chemistry / Pterins - immunology / Pterins - metabolism / Pterins - pharmacology / Salmonella - immunology / Salmonella - metabolism / Salmonella Infections - immunology / Salmonella Infections - microbiology / Science / Static Electricity / T cell receptors / T cells / T-Lymphocytes - immunology / Virulence (Microbiology) / Vitamin B / Vitamin B complex / Yeasts