Oral Presentation Crystal36-AXAA Conference 2026

Molecular insights into the recognition mechanism of a headless lipid by Natural Killer T cell receptor (143300)

Praveena Thirunavukkarasu 1 , Tan-Yun Cheng 2 , Srinath Govindarajan 3 4 , Catarina F. Almeida 5 , Daniel G. Pellicci 5 , Wellington C. Arkins 2 , Ildiko Van Rhijn 2 , Koen Venken 3 4 , Dirk Elewaut 3 4 , Dale I. Godfrey 5 , D. Branch Moody 2 , Jamie Rossjohn 1 6
  1. Infection and Immunity Program, Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  2. Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  3. Molecular Immunology and Inflammation Unit, Vlaams Instituut voor Biotechnologie, Center for Inflammation Research, Ghent University, Ghent, Belgium
  4. Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology unit), Ghent University, Ghent, Belgium
  5. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity,, University of Melbourne, Melbourne, Victoria, Australia
  6. Institute of Infection and Immunity, Cardiff University, Heath Park, Cardiff, UK

In the absence of foreign lipids, Natural Killer T (NKT) cells via their surface-expressed receptors display self-reactivity in conditions like autoimmunity, tumour immunity and graft-versus-host disease. Identifying the nature of self-lipids is a central aspect of understanding NKT cell self-reactivity. Using a high-throughput lipidomics approach, we identified self-lipids bound to the antigen-presenting molecule CD1d from mammalian cells, which lacked the polar sugar head group that normally serves as an epitope involved in NKT T cell receptor (TCR) recognition. We provide the first structural evidence, using X-ray crystallography, that the NKT TCR recognises the CD1d-presenting headless lipid antigen through a parallel docking orientation, positioning directly over the F’-pocket of CD1d. Surprisingly, the majority of intermolecular interactions in the complex were formed between CD1d and TCR itself, with minimal interactions in contacting the lipid. The absence of the sugar headgroup abolished key interactions it normally displays with the NKT TCR, but the overall conserved docking pattern was maintained. Surface Plasmon Resonance experiments showed that the NKT TCR bound the CD1d-headless lipid complex with micromolar affinities, which fall within the physiological range for activating ligands. Collectively, this study provides the first detailed molecular insights into how a CD1d presenting a headless lipid is structurally recognised by the NKT TCR. Our data provides proof of concept that small naturally occurring headless lipids could function as CD1d ligands in activating NKT cells.

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(* denotes co-first authors)

Cheng TY*, Praveena T*, Govindarajan S*, Almeida CF*, Pellicci DG, Arkins WC, Van Rhijn I, Venken K, Elewaut D, Godfrey DI, Rossjohn J, Moody DB. Lipidomic scanning of self-lipids identifies headless antigens for natural killer T cells PNAS. 2024 Aug 20;121(34):e2321686121.