γδ TCR ligands: the quest to solve a 500-million-year-old mystery

gamma delta T cells have been retained as a lineage over the majority of vertebrate evolution, are able to respond to immune challenges in unique ways, and are of increasing therapeutic interest. However, one central mystery has endured: the identity of the ligands recognized by the gamma delta T cell antigen receptor. Here we discuss the inherent challenges in answering this question, the new opportunities provided by recent studies, and the criteria by which the field might judge success.