Science Bite (3 min Oral Presentation) Lorne Infection and Immunity 2019

The structural and molecular insights into CD1d-glycolipid and natural killer T cell receptor recognition (#87)

Praveena Thirunavukkarasu 1 , Jérôme Le Nours 1 2 , Daniel G Pellicci 3 4 , Nicholas A Gherardin 3 , Fiona J Ross 3 , Ricky T Lim 3 , Gurdyal Besra 5 , Santhosh Keshipeddy 6 , Stewart K Richardson 6 , Amy R Howell 6 , Stephanie Gras 1 2 , Dale I Godfrey 3 4 , Jamie Rossjohn 1 2 7
  1. Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  2. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Australia, Melbourne, Victoria, Australia
  3. Microbiology and Immunology, Peter Doherty institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  4. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
  5. School of Biosciences, , University of Birmingham, Edgbaston, Birmingham, UK
  6. Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA
  7. Institute of Infection and Immunity, Cardiff University, Heath Park, Cardiff, UK

The immunological synapse is central to initiate an immune response, achieved by interaction between the antigen presented by CD1d and its cognate T cell receptor expressed on T lymphocytes. A population of innate-like T cells named as Natural killer T cells recognize lipid antigens presented on the Major Histocompatibility Complex (MHC)-like molecule CD1d. NKT cells have gained their therapeutic importance due to their ability to release an array of Th1 and Th2 cytokines that modulate a variety of immune responses ranging from infection to cancer. The two main subsets that are widely studied both in mice and humans are type I and type II. Type I NKT cells typically express an invariant α-chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a broad spectrum of β-chains (Vβ8.2, Vβ7 and Vβ2 in mice and Vβ11 in humans) and recognize α-Galactosylceramide (α-GalCer). Type II NKT cells express a diverse TCR repertoire and do not recognize α-GalCer. We have identified a new subset of NKT cells in humans that do recognize α-GalCer presented by CD1d but express TCRs with different gene usage from that of type I NKT cells and are termed as ‘Vα24- or atypical TCRs’. As α-GalCer is undergoing phase I/II clinical trials, it is important to understand the entire repertoire of α-GalCer reactive NKT cells in order to achieve an effective immune response. In our present study, we have solved the crystal structures of two atypical NKT TCRs in complex with CD1d/α-GalCer and investigated the structural and molecular basis of glycolipid recognition. Thus, our results shed light in understanding the mechanism of lipid antigen recognition and would aid in designing new immunotherapeutic agents to modulate immune responses in various clinical settings. The work described here has been published in Nature communications journal, 2016.