Atypical Natural Killer T-cell receptor recognition of CD1d-lipid antigens — ASN Events
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Atypical Natural Killer T-cell receptor recognition of CD1d-lipid antigens (#123)

Jerome Le Nours 1 2 , Praveena Thirunavukkarasu 1 2 , Dan G Pellicci 3 4 , Nicholas A Gherardin 3 5 , Ricky T Lim 3 , Gurdyal Besra 6 , Santosh Keshipeddy 7 , Stewart K Richardson 7 , Amy R Howell 7 , Stephanie Gras 1 2 , Dale I Godfrey 3 4 , Jamie Rossjohn 1 2 8 , Adam P Uldrich 3 4
  1. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute-Monash University, Clayton, Victoria, Australia
  2. Australian Research Council Centre of Excellence for Advanced Molecular Imaging-Monash University, Clayton, Victoria, Australia
  3. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity-University of Melbourne, Parkville, Victoria, Australia
  4. Australian Research Council Centre of Excellence for Advanced Molecular Imaging-University of Melbourne, Parkville, Victoria, Australia
  5. Cancer Immunology Research Program-Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  6. School of Biosciences-University of Birmingham, Birmingham, UK
  7. Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA
  8. Institute of Infection and Immunity-School of Medicine-Cardiff University, Cardiff, UK
The T lymphocytes repertoire is divided into two major lineages, αβ and γδ T cells [1, 2], that are defined by their T cell receptor (TCR) gene-segment usage. To date, most of the groundbreaking discoveries on human CD1d-α-galactosylceramide (α-Galcer) reactive T cells have focussed on the type I Natural Killer T cells (NKT) subset that express an invariant TCR α- chain (TRAV10-TRAJ18) which pairs with a β- chain (TRBV25-1). The structural basis for the recognition of CD1d-lipid antigen by type I NKT cells is also now well established [3, 4]. However, the extent of the diversity of the NKT cell repertoire is still unclear. Here, we identified a TRAV10-TRAJ18-TRBV25-1- population of human CD1d-α-Galcer reactive NKT cell subsets that expressed notably the atypical TRAV21-TRAJ8-TRBV7-8 and TRAV12-3-TRAJ27-TRBV6-5 αβ TCRs. The crystal structures of both αβ TCRs were determined in complex with CD1d-α-Galcer. The αβ TCRs dock orthogonally over the A' pocket of CD1d that is in clear contrast to the typical type I parallel docking mode in which the αβ TCR is perched over the F' pocket of CD1d. These findings highlight the emergence of diverse populations of NKT TCRs that exhibit different binding mode and lipid antigen specificity.
  1. Uldrich & Le Nours et al. CD1d-lipid antigen recognition by the γδ TCR. Nature Immunol., 2013.
  2. Luoma et al. Crystal structure of Vδ1 T cell receptor in complex with CD1d sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity, 2013.
  3. Borg et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T cell receptor. Nature, 2007.
  4. Wun et al. A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR. J. Exp. Med., 2008.