News

Unlike regular T cells which can recognise a wide range of harmful protein-breakdown products, NKT cells specialise in recognising lipids (fat-like molecules) from pathogens or the body’s own cells. 

In a study published in the Proceedings of the National Academy of Sciences (PNAS), an international team of scientists from Australia, USA and Belgium used advanced lipidomics – the large-scale study of cellular lipids and their roles in biological systems, cellular and structural immunology – to identify new natural lipid molecules that accumulate during cell stress to activate NKT cells.  

Together with Dr Tan-Yun Cheng and Professor Branch Moody from Harvard University, USA and Dr Srinith Govindrath and Professor Dirk Elewaut from Ghent University, Belgium the University of Melbourne’s  Dr Catarina Almeida, a Postdoctoral Research Fellow at the Doherty Institute and co-first author of the study, used a highly sensitive system to identify cellular lipids extracted from cells undergoing cellular stress.  

Dr Almeida said this technology, developed in a collaboration between the University of Melbourne and Harvard University, isolates lipids that promote binding by the NKT cell receptor, providing a powerful screen for novel antigenic targets for these T cells.  

“We found a new class of lipid molecules that we didn’t think could activate NKT cells,” said Dr Almeida. 

“Typically, NKT cells recognise lipid-molecules when a small part of them, known as the head-group, sticks out from the carrier protein, termed ‘CD1d’, that presents them.  

“However, the lipids identified here, which we call ‘headless antigens’, lack the part that normally sticks out. Thus, these lipids ‘hide’ inside the CD1d molecule and yet, despite their seclusion, NKT cells can still detect the presence of these headless lipids.” 

A crystal structure of this interaction was solved by co-first author Dr Praveena Thirunavukkarasu and Professor Jamie Rossjohn from Monash University. This showed how these lipids are detected at the molecular level through a process referred to as ‘absence of interference’ where the lack of a lipid head-group allows the NKT cell receptor to more closely approach and directly bind to, the CD1d proteins on the surface of cells that carry these lipids.  

The findings suggest that these headless lipids are responsible for activating NKT cells during cellular stress and associated immune responses, as reported in an earlier study by research collaborator Professor Elewaut from Ghent University, Belgium.  

The University of Melbourne’s Professor Dale Godfrey, Laboratory Head at the Doherty Institute and co-senior author of the study, said this research opens new possibilities for understanding immune regulation during inflammation and diseases where these ‘headless’ lipids accumulate.  

 “In many diseases, such as cancer and autoimmune disorders, cells undergo stress that accumulate certain lipids. Understanding how NKT cells detect these lipids could lead to new treatments that enhance or regulate this immune response,” said Professor Godfrey.  

The researchers anticipate that advancements in lipidomics and metabolomics will further uncover the complex interactions between lipids and the immune system, potentially leading to innovative approaches to disease treatment and prevention. 

• Peer review: Cheng T Y, et al. Lipidomic scanning of self-lipids identifies headless antigens for Natural Killer T cells. Proceedings of the National Academy of Sciences (PNAS) (2024). DOI: 10.1073/pnas.232168612 

• Collaboration:  Ghent University (Belgium) Havard University (USA), Monash University, Cardiff University (UK) 

• Funding: Australian Research Council (ARC), CSL, National Institute of Health (NIH), National Health and Medical Research Council (NHMRC), Research Foundation-Flanders and Wellcome Trust.