The molecular bases of δ/αβ T cell-mediated antigen recognition

alphabeta and gammadelta T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the alphabeta and gammadelta T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term delta/alphabeta T cells, expressing TCRs comprised of a TCR-delta variable gene (Vdelta1) fused to joining alpha and constant alpha domains, paired with an array of TCR-beta chains. We demonstrate that these cells, which represent approximately 50 of all Vdelta1+ 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 delta/alphabeta T cells recognized alpha-galactosylceramide (alpha-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as alpha-glucosylceramide, was distinct from type I NKT cells. Thus, delta/alphabetaTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how delta/alphabetaTCRs bind to their targets, with the Vdelta1-encoded region providing a major contribution to delta/alphabetaTCR binding. Our findings highlight how components from alphabeta and gammadeltaTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.