MAIT cells (yellow) identified by MR1-5-OP-RU tetramer (green) and CD3 (red) costaining, predominantly reside in T cell zones of lymph nodes. Blue depicts cell nuclei (DAPI) and yellow lines separate T cell zones from B cell zones. Tissue derived from Vα19Jα33 T cell receptor transgenic mice.
“Imaging CoE scientists developed novel biochemical reagents (MR1 tetramers) that have enabled the phenotypic characterisation of MAIT cells.”
In 2012, Imaging CoE Centre scientists made the startling find that an abundant T cell population, termed Mucosal-associated invariant T (MAIT) cells were activated by metabolites of vitamin B (namely riboflavin) (Nature 2012).
Using a combination of chemistry, cellular immunology and structural biology, they subsequently showed that the most potent MAIT cell antigen arose from the convergence of two distinct metabolic pathways, namely riboflavin metabolism and metabolites from glycolysis (Nature 2014).
Armed with this information, the field is now empowered to understand MAIT cells in homeostasis, health and disease. To further enable this, Imaging CoE scientists developed novel biochemical reagents (MR1 tetramers) that have enabled the phenotypic characterisation of MAIT cells.
PROF. JAMIE ROSSJOHN
PROF. DALE GODFREY
PROF. DAVID FAIRLIE
AT A GLANCE
Work in this area has helped establish:
- A greater understanding of the complexity of MAIT cell phenotypes in humans and problems with pre-MR1 tetramer based identification of these cells (ICB).
- The role of MAIT cells in transplantation (JCI).
- The role of MAIT cells in infection (JI and Nature Comms).
- The involvement of MAIT cells in multiple myeloma (Scientific Reports).
- Continue investigations into MAIT cell antigen recognition and activation.
- Exploring what other ligands bind MR1.
- Investigate role of MAIT cells and other MR1-restricted T cells in immune regulation.
Human blood MAIT cell subsets defined using MR1 tetramers
For many years, MAIT cells have been identified based on the expression of a combination of cell surface markers (CD3, CD8, CD161 and TRAV1-2). This is the basis for literally hundreds of studies of these cells. Based on our studies identifying the antigen specificity of MAIT cells for riboflavin derivatives (especially 5-OP-RU), and the use of this information to develop MR1-5-OP-RU tetramers to specifically identify MAIT cells, we have identified and characterised 5 distinct subsets of human MAIT cells, based on CD4, CD8α and CD8β coexpression: CD4+CD8-, CD4+CD8+, CD4-CD8-, CD4-CD8α+CD8β-, CD4-CD8α+CD8β+.
Further subdivision of MAIT cells was also apparent using other cell surface markers, such as CD56, NKG2D and other cell surface receptors. This highlights the fact that MAIT cells are a heterogeneous mix of cells and it is important to understand the developmental and functional relationship between these cell populations. We also demonstrated an unexpected correlation between the frequency of MAIT cells, NKT cells and γδT cells in human peripheral blood and show that the CD4+CD8- MAIT cell subset differs from the others with regard to cytokine production, and population kinetics with age.
This study also compared the populations defined by MR1 tetramer to the earlier techniques for identifying MAIT cells by surrogate cell surface markers CD3, CD8, CD161, TRAV1-2. While these previous techniques for identifying MAIT cells are reasonably accurate for studying CD8+ MAIT cells, in most but not all, healthy human samples; they were less effective for isolating CD8- MAIT cells and poor at isolating CD4+ MAIT cells. This highlights the need for caution in interpreting earlier studies of MAIT cells where surrogate markers were used.
Human blood MAIT cell subsets defined using MR1 tetramers. Gherardin NA, Souter MN, Koay HF, Mangas KM, Seemann T, Stinear TP, Eckle SB, Berzins SP, d’Udekem Y, Konstantinov IE, Fairlie DP, Ritchie DS, Neeson PJ, Pellicci DG, Uldrich AP, McCluskey J, Godfrey DI. Immunol Cell Biol. 2018 May;96(5):507-525. doi: 10.1111/imcb.12021. Epub 2018 Mar 25
MR1-restricted T cells, defined using MR1 tetramers, are more diverse than generally appreciated. These include at least three distinct cell types based on TCR usage, cell surface phenotype, and transcription factor expression.
Image: Gherardin, N. A., J. McCluskey, J. Rossjohn, and D. I. Godfrey. 2018. The Diverse Family of MR1-Restricted T Cells. J Immunol 201: 2862-2871.
Dr Daniel Pellicci wins top award for research into immune system ‘first responders’
Dr Daniel Pellicci, who has dedicated his career to solving the mysteries of the immune system, won the Commonwealth Health Minister’s Award for Excellence in Health and Medical Research for 2018.
University of Melbourne’s Dr Daniel Pellicci, Senior Research Fellow from the Imaging CoE and The Peter Doherty Institute for Infection and Immunity, focuses on the ‘first responders’ of the immune system, particularly the roles of cells known as unconventional T cells.
These cells kick-start an immune response and can recruit other aspects of the immune system within minutes to mount a comprehensive fight against infection.
“With a better understanding of these T cells, we could potentially exploit them to treat human disease. In fact, some of them are already being trialled as immunotherapeutic targets to fight cancer and infections,” Dr Pellicci said.
“I’m tremendously excited to receive the Commonwealth Health Minister’s Award and to have my work as a cellular immunologist recognised in this way.”
Imaging CoE Chief Investigator Professor Dale Godfrey, who heads a laboratory at the Doherty Institute, said Dr Pellicci is emerging as a key international player in this field of immunology research.
“Daniel’s enthusiasm and dedication to his work is exemplary. He has always taken great pride in his work and it’s been a great pleasure to see him moving his way up the ladder with many great achievements and high-impact papers along the way,” Professor Godfrey said.
“This honour is well-deserved and I look forward to ongoing collaborations with Daniel as he establishes his own laboratory in the near future.”
Dr Pellicci is very passionate about turning his focus to understanding how these T cells work in the context of Mycobacterium Tuberculosis (TB).
“It’s not acceptable that over a million people continue to die from TB every year. I would like to find a way to exploit unconventional T cells to potentially boost the current BCG vaccine, and reduce the number of people dying from this devastating disease,” he said.
The Commonwealth Health Minister’s Award for Excellence in Health and Medical Research recognises outstanding individual achievement by a mid-career Australian researcher. Dr Pellicci received the medal and $50,000 to help further his research at the Australian Society for Medical Research (ASMR) Victorian Gala Dinner.
Dr Daniel Pellicci