Le Nours Lab research
About Dr Jérôme Le Nours
Jérôme works in the Faculty of Medicine, Nursing and Health Sciences (Monash Biomedicine Discovery Institute) at Monash University as an Australian Research Council (ARC) Future Fellow. Jerome was initially trained as a chemist at the University of Brest (France) prior to the completion of his PhD in structural biology at the University of Copenhagen (Denmark) in 2005. During his PhD, he acquired a set of skills and expertise in a range of biophysical techniques that enabled him to complete a very successful PhD with the publication of a total of five peer-review articles (four as first author). He then pursued his scientific career as a research fellow at the University of Auckland (New Zealand) where he studied the protein structures of Mycobacterium tuberculosis. In 2008, Jérôme relocated to Australia and accepted a research fellow position at Monash in the Department of Biochemistry and Molecular Biology, where he expanded his interest and skills in immunity and structural biology. Since then, he has established an impressive track record with the publication in top-tier generalist journals such as Nature and Nature Communications, and in very prestigious high impact journals in the field of immunology such as Nature Immunology, Immunity and The Journal of Experimental Medicine. Of particular significance are Jerome’s contributions to the field of MHC-like (Major Histocompatibility Complex)-mediated T-cell immunity. In 2016, Jérôme was awarded a prestigious ARC Future fellowship, and in 2017, he was appointed as an independent group leader within the Biomedicine Discovery Institute (Monash University). By applying a multi-disciplinary and highly innovative approaches that include comparative immunology, chemistry, structural biology, cell immunology, advanced atomic and molecular imaging, his research program aims to provide comprehensive and fundamental insights into molecular recognition of non-peptidic antigens (Ags), and gain an evolutionary perspective on the structure and function of MHC-like Ag-presenting molecules.
- Recognition of self-lipid antigens by type 2 Natural Killer T cells.
- Investigating diversity within the MR1-restricted T cell repertoire in humans.
- An investigation into aberrant T cell reactivity towards lipids.
Our research activities aim to provide comprehensive and fundamental insights into molecular recognition of non-peptidic antigens, and gain an evolutionary perspective on the structure and function of MHC-like Ag-presenting molecules. Our research program is divided into three main themes:
1. Investigating the CD1 family and lipids-mediated immunity
Presently, greatest progress in this field has been centered on CD1d, and its recognition by a subset of T-cells termed, Natural Killer T cells (NKT cells), and my team made sustained contributions regarding NKT TCR recognition of CD1d. An exciting new direction arising from my recent findings relates to atypical ab, d-ab and gd TCRs recognition of lipid-based Ags presented by CD1d. Through structural studies, we unravelled the molecular mechanisms that underpin the recognition of lipid-based antigen presented by atypical populations of CD1d-restricted ab, d-ab and γδ T-cells. Our findings greatly expanded our understanding of T-cell biology and radically reshaped our understanding of NKT TCR recognition. However, there is very limited information relating to TCR molecular recognition of the group 1 CD1 family members. Our understanding of CD1a, b and c reactive T-cells, which include ab TCRs and gd TCRs, and their biotechnological potential is extremely limited, despite their obvious importance, as evidenced by the fact that they represent a major component of the immune response to M. tuberculosis. The role of lipid-reactive T-cells in other infections and diseases such as autoimmunity is unknown and accordingly we need to understand the biological function of lipid-antigen reactive T-cell populations. Exciting, major questions that we aim to address include: what specific antigens do they respond to, what role do they play in protective immunity, what impact do they have on autoimmunity? However, a major stumbling block in this entire field is the requirement to chemically synthesise these complex lipid-based reagents, and then developing protocols to selectively load these scarce reagents. Accordingly, we have established collaborations with chemists to synthesise CD1-restricted ligands, and moreover have developed mass spectrometry expertise that will allow us to identify novel lipid antigens bound to CD1. Using such reagents, we then aim to characterise the T-cell repertoire and the molecular basis of TCR-CD1-lipid interactions across the entire group 1 CD1 family.
Figure 1. Molecular recognition of CD1d-lipid Ag by atypical ab TCRs.
2. Investigating the MR1 family and metabolites-mediated immunity.
Mucosal Associated Invariant T (MAIT) cells are an abundant population of T cells in mammals that are mostly found in the mucosa. While the physiological role of MAIT cells is emerging, it is established that numerous bacteria and yeast activate MAIT cells (whereas viruses do not), which indicated that MAIT cells respond to a conserved Ag(s) common to these activating microbes. MAIT cells function via the MAIT TCR, an “invariant” TCR that is restricted to the ubiquitously expressed molecule, MR1. Here, a major stumbling block was that the nature of the antigen that activates MAIT cells was unknown. My team was part of a collaborative effort that made the paradigm-shifting discovery that MR1 presents vitamin B metabolites to MAIT cells, and provided a structural basis underpinning MAIT TCR recognition of folic acid derivatives and riboflavin precursors. Moreover, we recently demonstrated that the MAIT TCRs repertoire is more diverse than originally envisaged, where MR1-mediated T-cell immunity can indeed be orchestrated by T-cells other than MAIT, and this diversity can manifest in different docking modes on MR1. Clearly, we are just at the tip of the iceberg in understanding MAIT TCRs structure and function, and we embarked on a series of studies to further this field. Key questions that we want to address are: (i) What is the range of antigens that MAIT cells respond to? (ii) What are the factors that determine the extent to which vitamin B metabolites can activate/inhibit MAIT cells? (iii) What is the full extent of the MR1-restricted T-cells repertoire?
Figure 2. MR1-mediated recognition by T cells.
3. To explore the field of comparative immunology (Structure and function of MHC-like molecules in evolutionary distinct species, e.g. Marsupials, frogs, and bats).
In the past decade, the development of technologies (e.g. genomics and proteomics) has opened new exciting frontiers and novel opportunities to explore the diversity of immunity in mammalian and non-mammalian species. There is indeed tremendous value and excitement to discover how the immune system in different organisms (non-human, non-mouse) work, and more importantly to understand how distant species adapted to their immediate environment in order to survive exposure to pathogens throughout evolution. Addressing these fundamental questions may have significant impact in relation to the origin and function of the immune system. Here, we investigate the biological function of MHC-like molecules in evolutionary distinct species to humans. We have established international collaborations with comparative immunologists who are experts in the evolutionary study of the immune system of specific species.In essence,this research activity focusses on the functional and structural studies of 4 families of MHC-like from a wide range of vertebrate species spanning more than 360 millions years of evolution:
- Family of XNCs molecules from the amphibian Xenopus laevis.
- Family of UT molecules from marsupials (e.g. Opossums, koalas and Tasmanian devils) and monotremes (e.g. Platypus).
- Family of MHX molecules from vertebrate species (e.g. rabbits, squirrels and armadillos).
- MR1 orthologs from mammalian species (e.g. bats, pigs, and cows).
Collectively, these four separate proposed studies provide a fantastic opportunity to: (i) discover possible novel classes of antigens presented by ancestral immune molecules, and presently unknown; (ii) explore immune recognition across species; (iii) provide fundamental molecular insights into the evolution of immunity.
Our research involves a broad range of disciplines that includes molecular biology, chemistry, protein chemistry, molecular imaging (X-ray crystallography) and Surface Plasmon Resonance. To conduct our research, the team has access to key national infrastructure such as the Australian National Synchrotron and to state-of-the-art expertise and technology within the ARC CoE in Advanced Molecular Imaging.
We collaborate with many scientists and research organisations around the world. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).
Student research projects
The Le Nours Lab offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short term research opportunities available.
Please visit Supervisor Connect to explore the projects currently available in our Lab.