Invited Speaker CD1-MR1 Workshop 2025

A little bit on the side (#11)

Jamie Rossjohn 1 2 , Thinh-Phat Cao 1 , Guan-Ru Liao 1 , Tan-Yun Cheng 3 , Yanqiong Chen 1 , Laura Ciacchi 1 , Thomas S Fulford 4 , Rachel Farquhar 1 , Jade Kollmorgen 1 , Jacob A Mayfield 3 , Adam P Uldrich 4 , Emily Zhi Qing Ng 5 , Graham S Ogg 5 6 , Dale I Godfrey 4 , Nicholas A Gherardin 4 , Yi-Ling Chen 5 6 , D. Branch Moody 3 , Adam Shahine 1
  1. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC, Australia
  2. Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, United Kingdom
  3. Division of Rheumatology, Immunity and Inflamation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  5. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
  6. MRC Translational Immune Discovery Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom

For the MHC, MR1 and CD1 systems, antigen recognition involves contact of the membrane distal surfaces of the ab T cell receptor (TCR) and the antigen presenting molecule.  Here we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive abTCR. CD1c bound lipids with bulky headgroups that could not fit within the tight TCR-CD1c interface. We determined the crystal structures of CD1c presenting several gangliosides, revealing a general mechanism whereby two lipids, rather than one, are bound in the CD1c cleft. Bulky lipids were orientated sideways so that their polar headgroups protruded laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways presented ganglioside headgroups did not hinder TCR binding and so represent a mechanism  that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed sideways presented gangliosides could also represent TCR recognition determinants. These findings reveal a general mechanism whereby CD1c simultaneously presents two lipid antigens from the top and side of its cleft that differs markedly from other antigen-presenting molecules.