Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor

How γδ T cells 'see' antigen is poorly defined. Déchanet-Merville and colleagues demonstrate that a subset of γδ T cells functionally recognize the stress-associated self molecule EPCR on both virus-infected and transformed cells. T cells bearing γδ T cell antigen receptors (TCRs) function in lymphoid stress surveillance. However, the contribution of γδ TCRs to such responses is unclear. Here we found that the TCR of a human V γ 4V δ 5 clone directly bound endothelial protein C receptor (EPCR), which allowed γδ T cells to recognize both endothelial cells targeted by cytomegalovirus and epithelial tumors. EPCR is a major histocompatibility complex–like molecule that binds lipids analogously to the antigen-presenting molecule CD1d. However, the V γ 4V δ 5 TCR bound EPCR independently of lipids, in an antibody-like way. Moreover, the recognition of target cells by γδ T cells required a multimolecular stress signature composed of EPCR and costimulatory ligand(s). Our results demonstrate how a γδ TCR mediates recognition of broadly stressed human cells by engaging a stress-regulated self antigen.