γδ T cell responses: How many ligands will it take till we know?

γδ T cells constitute a sizeable and non-redundant fraction of the total T cell pool in all jawed vertebrates, but in contrast to conventional αβ T cells they are not restricted by classical MHC molecules. Progress in our understanding of the role of γδ T cells in the immune system has been hampered, and is being hampered, by the considerable lack of knowledge regarding the antigens γδ T cells respond to. The past few years have seen a wealth of data regarding the TCR repertoires of distinct γδ T cell populations and a growing list of confirmed and proposed molecules that are recognised by γδ T cells in different species. Yet, the physiological contexts underlying the often restricted TCR usage and the chemical diversity of γδ T cell ligands remain largely unclear, and only few structural studies have confirmed direct ligand recognition by the TCR. We here review the latest progress in the identification and validation of putative γδ T cell ligands and discuss the implications of such findings for γδ T cell responses in health and disease.