Plasticity in CD1d-lipid antigen recognition by non-canonical NKT cells — ASN Events
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Plasticity in CD1d-lipid antigen recognition by non-canonical NKT cells (#96)

Catarina F Almeida 1 2 , Srinivasan Sundararaj 3 4 , Jérôme Le Nours 3 4 , Onisha Patel 3 , Benjamin Cao 5 , Daniel G Pellicci 1 2 , Spencer Williams 5 , Jamie Rossjohn 3 4 6 , Adam P Uldrich 1 2 , Dale I Godfrey 1 2
  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne , Melbourne, VIC, Australia
  2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences , Monash University, Melbourne, Clayton, Australia
  4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Monash, VIC, Australia
  5. School of Chemistry , Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia
  6. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK

Natural Killer T (NKT) cells are specialised lymphocytes that recognise lipid antigens presented by the MHC Class I-like molecule CD1d. Following activation, they rapidly secrete a broad range of immunoregulatory cytokines that can influence other mediators of immune responses and therefore they represent a promising therapeutic target for cancer and other diseases. The most extensively studied are type 1 NKT cells, which recognise a derivative of a marine sponge glycolipid α-galactosylceramide (α-GalCer), express a semi-invariant T cell receptor (TCR) and have a well-established role in the immune system. Much less is known about type 2 NKT cells, which do not recognise α-GalCer and express a diverse TCR repertoire. Using a panel of CD1d mutants, we reveal that different type 2 NKT cell hybridomas can adopt multiple ways to interact with CD1d, and furthermore, we identify a new population of type 2 NKT cells that specifically recognises the microbial derived lipid-antigen α-glucuronosyl-diacylglycerol (α-GlcA-DAG). Single cell sequencing of these cells reveals a polyclonal TCR repertoire distinct from type 1 NKT cells. Collectively, our results suggest that type 2 NKT cells express highly diverse TCRs and rely on mechanisms different to type 1 NKT cells to recognise distinct antigens. The knowledge obtained from these studies increases the scope of antigens recognized by NKT cells and provides valuable insight in how these cells can be manipulated for therapeutic purposes.