Flash Talk & Poster CD1-MR1 2024

Insights into the molecular recognition mechanism of a headless lipid by type I Natural killer T cell receptor (#131) (#14)

Praveena Thirunavukkarasu 1 , Tan-Yun Cheng 2 , Srinath Govindarajan 3 4 , Catarina F. Almeida 5 , Daniel G. Pellicci 5 6 7 , Ildiko Van Rhijn 2 8 , Dirk Elewaut 3 4 , Dale I. Godfrey 5 6 , D. Branch Moody 2 , Jamie Rossjohn 1 9
  1. Infection and Immunity program & Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  2. Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  3. Unit for Molecular Immunology and Inflammation,, VIB-Center for Inflammation Research,, Ghent, Belgium
  4. Department of Internal Medicine and Pediatrics,, Ghent University, , Ghent, Belgium
  5. Microbiology and Immunology, Peter Doherty institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  6. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
  7. Cellular Immunology Group,, Murdoch Children's Research Institute,, Melbourne, Victoria, Australia
  8. Department of Infectious Diseases and Immunology,, Faculty of Veterinary Medicine, Utrecht University,, Utrecht,, Netherlands
  9. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Australia, Melbourne, Victoria, Australia

In the absence of foreign lipids, Natural killer T (NKT) cells 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 have identified CD1d-bound self-lipids from mammalian cells, which lacked the polar sugar head group that normally serves as an epitope for NKT T cell receptor (TCR) recognition. Our X-ray crystallography studies of a type I NKT TCR binding of CD1d-presenting headless lipid antigen revealed the TCR adopted a parallel docking topology positioning itself atop the F’-pocket of CD1d. Surprisingly, the majority of the 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, nevertheless, the overall conserved docking pattern was maintained. Of note, the NKT TCR bound the CD1d-headless lipid with micromolar affinities as measured by SPR. Collectively, this study provides the first detailed insights into how a CD1d-presenting headless antigen 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 the context of NKT cells.