An overview of the research and its implications, the abstract of the paper, and background information on the ARC Centre of Excellence in Advanced Molecular Imaging.
T-cell activation by transitory antigens
Summary
Mucosal associated invariant T cells (MAIT cells) are an abundant population of T cells, that are prominent in the liver and the lining of the gut. We identified a family of compounds to which MAIT cells bind. They are derived from the building blocks of bacterial vitamin B. This is a major breakthrough as it allows us to work out the function of MAIT cells and how they operate. Our findings have implications for immunity, and the dietary intake of vitamin-B containing foods. Our fundamental discovery has very real clinical potential. It should pave the way to unravelling the role of MAIT cells in health and immunopathology—particularly in chronic inflammatory diseases—and to providing diagnoses and treatments for human diseases.
Research overview
Our research has resulted in a fundamental advance in understanding immunity, by defining the particular compounds that activate mucosal associated invariant T-cells (MAIT). Found in the liver and at mucosal surfaces, these cells comprise 10% of all the T-cells in the blood. Our success at determining the compounds that trigger MAIT cells provides us with a major clue as to how they contribute to immunity – knowledge that will help us forge new clinical pathways to treating chronic inflammatory diseases like TB, peptic ulceration, periodontal disease, and inflammatory bowel disease.
MAIT cells are activated by antigen compounds bound to MR1 proteins. We showed that the structure of MR1 was suited to binding antigens originating from the building blocks of vitamins. These antigens are only found in bacteria and fungi. In contrast to the MHC and CD1 families of proteins, MR1 can present folic acid (vitamin B9) and riboflavin (vitamin B2) metabolites, the latter of which activate MAIT cells. We showed that the immune system is triggered by these vitamin building blocks, which represent a new class of antigen for T-cell surveillance. This has implications for way diet can influence MAIT activity, and for whether other microbial compounds can affect and change MAIT cell function. Our findings will be pivotal in understanding the role of MAIT cells in the body, and in promoting their possible use in clinical practice.
Implications
While MAIT cells comprise a remarkable 10% of all T-cells in the blood, they are unknown in clinical practice. Their role in immune protection and in immunopathology is not established, particularly in chronic inflammatory diseases like TB, peptic ulceration, periodontal disease and in inflammatory bowel disease. The identification of a family of compounds derived from bacterial vitamin metabolites to which MAIT binds is a major breakthrough, as it allows assessment of their role. Defining the nature of the compounds that bind to MAIT cells will pave the way to a detailed understanding of their role in immunity. Directing MAIT cell activity becomes possible through the development of vaccines and antagonists that can manipulate MAIT cell functions according to their role. Our present work has very real clinical potential in unravelling the role of MAIT cells in health and disease, and in determining potential diagnostic and therapeutic compounds to combat human disease.
Abstract
T-cell activation by transitory neo-antigens derived from distinct microbial pathways
Full paper from Nature: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13160.html
T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids. Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells, an abundant population of innate-like T cells in humans. However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the Major Histocompatibility Complex related protein, MRI, are not well understood.
We show here that MAIT cell activation requires key genes encoding enzymes that form 5-amino-6-D-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. While 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways.
The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible covalent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT Ags are present in a range of microbes.
Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT cell immunosurveillance.
Senior authors
- Prof Jamie Rossjohn, Department of Biochemistry and Molecular Biology, Monash University & ARC Centre of Excellence in Advanced Molecular Imaging
- Dr David P. Fairlie, Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland & ARC Centre of Excellence in Advanced Molecular Imaging
- Prof James McCluskey, Department of Microbiology & Immunology, The University of Melbourne
- Dr Lars Kjer-Nielsen, Department of Microbiology & Immunology, The University of Melbourne
Lead author
- Dr Alexandra Corbett, Department of Microbiology & Immunology, The University of Melbourne
About the ARC Centre of Excellence in Advanced Molecular Imaging
The ARC Centre of Excellence in Advanced Molecular Imaging integrates physics, chemistry and biology to unravel the complex molecular interactions that define immunity.
The Centre will develop new imaging methods to visualise atomic, molecular and cellular details of how immune proteins interact and affect immune responses.
It will enable Australia to be an international leader in biological imaging, train the next generation of interdisciplinary scientists, and provide new insights into combating common diseases that afflict society.
About the Australian Synchrotron
The Australian Synchrotron is a source of highly intense light ranging from infrared to hard X-rays used for a wide variety of research purposes. The intense light it produces is filtered and adjusted to travel into experimental workstations, where the light reveals the innermost, sub-microscopic secrets of materials under investigation, from human tissue to plants to metals and more.
With the new knowledge that synchrotron science provides about the molecular structure of materials, researchers can invent ways to tackle diseases, make plants more productive and metals more resilient.
Officially opened in July 2007, the Australian Synchrotron is one of fewer than 40 similar facilities around the world.