Auguries of adaptivity: LES γδ TCR ligand recognition revisited

Identification of antigenic ligands for the γδ T cell receptor (TCR) has remained a highly challenging goal since the emergence in the 1980s of γδ T cells as a distinct immune compartment. 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 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. In this review 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.