Auguries of adaptivity: LES γδ-TCR ligand recognition revisited

Identification of antigenic ligands for the γδ-TCR T-cell-receptor (TCR) has remained a highly challenging goal since the emergence of γδ T-cells as a distinct immune compartment in the 1980s. In a significant advance more than 12 years ago, endothelial protein C receptor (EPCR), a cell-surface-expressed Major-Histocompatibility-Complex(MHC)-like protein that binds to phospholipids, was identified as the first ligand for a human γδ-TCR to be validated by direct binding experiments – a finding that undoubtedly posed more questions than it answered. Here we discuss how features of this single clonotypic specificity anticipated insights into adaptive-like human γδ T-cell biology that emerged in subsequent investigations, and we highlight recent findings about EPCR that point towards the relevance of such responses in anti-pathogen and potentially anti-tumour immunity.