The molecular bases of delta / alpha beta T cell-mediated antigen recognition

Godfrey, Rossjohn, and colleagues define a population of T cells in healthy humans that express T cell receptors (TCRs) comprised of delta variable gene segments fused to alpha joining and constant domains and paired with a variety of TCR- beta chains. Functional and structural analyses reveal how components of alpha beta and gamma delta TCR gene loci combine to create T cells with unique patterns of antigen recognition. alpha beta and gamma delta T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the alpha beta and gamma delta T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term delta / alpha beta T cells, expressing TCRs comprised of a TCR- delta variable gene (V delta 1) fused to joining alpha and constant alpha domains, paired with an array of TCR- beta chains. We demonstrate that these cells, which represent similar to 50% of all V delta 1+ 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 / alpha beta 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 / alpha beta TCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how delta / alpha beta TCRs bind to their targets, with the V delta 1-encoded region providing a major contribution to delta / alpha beta TCR binding. Our findings highlight how components from alpha beta and gamma delta TCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.