γδ T cell surveillance via CD1 molecules

• Vδ1+ γδ T cells engage CD1 molecules using a diverse structural footprint.
• The recognition of CD1d–lipid is dominated by the Vδ1 domain.
• The CDR3 loops make important contacts in lipid–antigen discrimination.
• Autoreactivity of Vδ1+ γδ T cells may be modulated by co-stimulatory signals.

γδ T cells are a prominent epithelial-resident lymphocyte population, possessing multi-functional capacities in the repair of host tissue, pathogen clearance, and tumor surveillance. Although three decades have now passed since their discovery, the nature of γδ T cell receptor (TCR)-mediated ligand recognition remains poorly defined. Recent studies have provided structural insight into this recognition, demonstrating that γδ T cells survey both CD1 and the presented lipid, and in some cases are exquisitely lipid specific. We review these findings here, examining the molecular basis for and the functional relevance of this interaction. We discuss potential implications on the notion that non-classical major histocompatibility complex (MHC) molecules may function as important restricting elements of γδ TCR specificity, and on our understanding of γδ T cell activation and function.