Lipids in Immunity: Presentation of lipid antigens (yellow) by lipid antigen presenting molecules (gold) for recognition by T cell receptors (orange) is a critical first step in lipid mediated T cell immunity.
“It is now becoming evident that the CD1 family can play an important role in both protective immunity and immunopathology.”
As well as T cells sensing peptides presented by MHC molecules (Theme 5), they can also respond to lipids (this theme) and metabolites (Theme 7). In the context of lipid-mediated immunity, TCRs recognise lipids that are presented by MHC-I like molecules, namely the CD1 family.
There are four members of the CD1 family of antigen-presenting molecules expressed on the cell surface (CD1a,b,c,d), each one of which possesses unique structural and biochemical/cellular features that indicates distinct roles in immunity. Indeed, it is now becoming evident – in part due to the contributions of Imaging CoE scientists, that the CD1 family can play an important role in both protective immunity (e.g. response to Mycobacterium tuberculosis) and immunopathology. Imaging CoE scientists continue to pioneer this aspect of immunity.
PROF. JAMIE ROSSJOHN
PROF. DALE GODFREY
AT A GLANCE
While most studies into lipid mediated immunity have centred on understanding how Natural Killer T (NKT) cells respond to lipids presented by the CD1d member, there is a major lack of understanding of T cell responses to the other CD1 family members (CD1a-c). The Imaging CoE is focused on bridging this basic knowledge gap.
Collectively, findings in this area has led to:
- Understanding of how TCRs recognise CD1c via a previously undescribed mechanism (Nature Immunology).
- How the different isoforms of CD1d play a key role in immunity (PNAS).
- How the fine chemical structure of lipid antigens modulate the immune response to NKT cells (Cell Chemical Biology).
- How lipid antigen recognition by NKT cells in liver can lead to enhanced CD8 T cell resident memory cells in liver (Cell Reports).
- How CD1d-lipid antigen reactive NKT cells are functionally diverse and how this response is shaped by the inflammatory environment at the time of activation (Immunol. Cell Biol.).
- Explore protective immune responses to lipid antigens.
- Examine CD1 auto reactivity in the context of health and autoimmunity.
T cell autoreactivity directed toward CD1c itself rather than toward carried self lipid
There are 4 CD1 isoforms – CD1a, CD1b, CD1c and CD1d. Imaging CoE scientists have pioneered our understanding of how TCRs recognise CD1d (Borg, Nature 2007), CD1a (Birkinshaw, Nature Immunology 2015) and CD1b
(Nature Comms 2016 & Science Immunology 2017).
A last bastion in gaining an understanding of the molecular basis of lipid mediated immunity was that of knowing how TCRs recognised CD1c plus lipid antigen. Understanding this is a key question as the 3D architecture of CD1c is distinct from other CD1 family members; it possesses a distinct tissue distribution from the other CD1 family members; and CD1c-restricted T cell immunity has been implicated in autoimmunity, tumour immunity, as well as immune responses to Mycobacterium tuberculosis. Yet, the particular role of T cell reactivity to CD1c in health and disease remained unknown and understanding how TCRs recognise this antigen-presenting molecule is central to filling this knowledge gap.
In the paper to the right, this is precisely what Imaging CoE scientists achieved. It had long been understood that many T cells exhibited autoreactivity towards CD1c, but the basic mechanism underpinning this was unknown. In collaboration with the Moody lab (Harvard), it was shown that TCRs could recognise CD1c directly, in a manner that did not involve co-recognition of the associated self-lipid antien.
This finding is in stark contrast to the co-recognition paradigm centric to peptide mediated immunity for which Zinkernagel and Doherty received the Nobel Prize (1996). Instead, small self-lipids were sequestered deep inside the CD1c molecule, stabilising this molecule while enabling the TCR to closely approach the CD1c molecule itself, whereas other lipid antigens essentially obstruct this recognition. This provided a model by which CD1c-restricted T cell responses are governed by lipid-mediated inhibition of CD1c recognition. As such, Centre scientists defined a new mechanism of TCR recognition.
Wun, K.S., Reijneveld, J.F., Cheng, T.Y., Ladell, K., Uldrich, A.P., Le Nours, J., Miners, K.L., McLaren, J.E., Grant, E.J., Haigh, O.L., Watkins, T.S., Suliman, S., Iwany, S., Jimenez, J., Calderon, R., Tamara, K.L., Leon, S.R., Murray, M.B., Mayfield, J.A., Altman, J.D., Purcell, A.W., Miles, J.J., Godfrey, D.I., Gras, S., Price, D.A., Van Rhijn, I., Moody*, D.B. & Rossjohn*, J. T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nature Immunol. 19, 397-406 (2018).
Image: Cotton et al. COI 2018
Professor Jamie Rossjohn awarded Royal Society of Victoria Medal for Excellence
Imaging CoE Chief Investigator Professor Jamie Rossjohn, Head of the Monash Biomedicine Discovery Institute’s (BDI) Infection and Immunity Program, was awarded the distinguished Royal Society of Victoria’s (RSV) Medal for Excellence in Scientific Research in Category II: Biomedical
and Health Sciences.
The Research Medal recognises peak research career achievements and outstanding leadership in research by scientists working in the State of Victoria.
He is currently an ARC Australian Laureate Fellow (2017-2021) and was previously a NHMRC Australia Fellow (2011-2016) and ARC Federation Fellow (2007-11).
RSV President David Zerman emphasised that the Medal is not just about discovery and innovation, but also about fostering and supporting a thriving research community and workforce to achieve collective impact.
“Some of this is demonstrated through a scholar’s personal output of journal articles and the related citations, or through patents and commercialisation, but it is also the research ecosystem that a leader supports through mentorship, collaboration and public engagement,” Mr Zerman said.
“We look very favourably on research leaders who bring effective teams together, and who actively promote younger scientists in particular, either through direct supervision, co-authorship of major papers, or simply creating opportunities for meaningful, purposeful work in an intensely competitive job market,” he said.
This year, the Medal was jointly awarded to both Professor Rossjohn and Professor Anthony Burkitt from Bionic Vision Australia and the Melbourne School of Engineering.
L-R Professor Anthony Burkitt, Her Excellency, the Honourable Linda Dessau AC, Governor of Victoria and Professor Jamie Rossjohn.
Image: Adrienne Bizzarri Photography.