Microbiology & Immunology - Research Publications

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Author: Godfrey, Dale × Author: Pellicci, Daniel × Author: ROSS, FIONA × Author: Rossjohn, Jamie ×

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    Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens
    Le Nours, J ; Praveena, T ; Pellicci, DG ; Gherardin, NA ; Ross, FJ ; Lim, RT ; Besra, GS ; Keshipeddy, S ; Richardson, SK ; Howell, AR ; Gras, S ; Godfrey, DI ; Rossjohn, J ; Uldrich, AP (NATURE PUBLISHING GROUP, 2016-02)
    Crucial to Natural Killer T (NKT) cell function is the interaction between their T-cell receptor (TCR) and CD1d-antigen complex. However, the diversity of the NKT cell repertoire and the ensuing interactions with CD1d-antigen remain unclear. We describe an atypical population of CD1d-α-galactosylceramide (α-GalCer)-reactive human NKT cells that differ markedly from the prototypical TRAV10-TRAJ18-TRBV25-1(+) type I NKT cell repertoire. These cells express a range of TCR α- and β-chains that show differential recognition of glycolipid antigens. Two atypical NKT TCRs (TRAV21-TRAJ8-TRBV7-8 and TRAV12-3-TRAJ27-TRBV6-5) bind orthogonally over the A'-pocket of CD1d, adopting distinct docking modes that contrast with the docking mode of all type I NKT TCR-CD1d-antigen complexes. Moreover, the interactions with α-GalCer differ between the type I and these atypical NKT TCRs. Accordingly, diverse NKT TCR repertoire usage manifests in varied docking strategies and specificities towards CD1d-α-GalCer and related antigens, thus providing far greater scope for diverse glycolipid antigen recognition.
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    The molecular bases of δ/αβ T cell-mediated antigen recognition
    Pellicci, DG ; Uldrich, AP ; Le Nours, J ; Ross, F ; Chabrol, E ; Eckle, SBG ; de Boer, R ; Lim, RT ; McPherson, K ; Besra, G ; Howell, AR ; Moretta, L ; McCluskey, J ; Heemskerk, MHM ; Gras, S ; Rossjohn, J ; Godfrey, DI (ROCKEFELLER UNIV PRESS, 2014-12-15)
    αβ and γδ T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the αβ and γδ T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term δ/αβ T cells, expressing TCRs comprised of a TCR-δ variable gene (Vδ1) fused to joining α and constant α domains, paired with an array of TCR-β chains. We demonstrate that these cells, which represent ∼50% of all Vδ1(+) human T cells, can recognize peptide- and lipid-based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive δ/αβ T cells recognized α-galactosylceramide (α-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as α-glucosylceramide, was distinct from type I NKT cells. Thus, δ/αβTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how δ/αβTCRs bind to their targets, with the Vδ1-encoded region providing a major contribution to δ/αβTCR binding. Our findings highlight how components from αβ and γδTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.