The adaptive immune system in jawed vetebrates comprises of B cells, αβ T cells and an ill-defined third lineage. γδ T cells have coevolved to fulfil unique roles immunological roles. This requires the γδ T cell receptor to recognise structurally-diverse ligands, including self-molecules in unprecedented ways. Cell activation is a tightly regulated by the γδ T cell receptor triggering complex.
Here, we will present our current understanding of γδ T cell activation. This will summarise recent work identifying and characterising novel ligands for human γδ T cells 1,2,3. This led to the cryo-EM structure of the enitre human γδ T cell triggering complex 4. The structure revealed that specificity conferring part of the complex was remarkably dynamic. Single molecule imaging and confocal microscopy showed that conformational heterogeneity occurred on a cell surface. Receptor engineering to create a rigid chimeric receptor altered receptor signalling. This revealed that the flexibility of the γδ T cell triggering complex was functional. This likely reflects a compromise between efficient signalling and a need to engage diverse ligands. Our findings revealed the remarkable structural plasticity of the T cell triggering complex on evolutionary timescales. These data offer insight into the distinct activation mechanisms of γδ T-cells that significantly advance our understanding of their unique immunobiology and immunotherapies targeting these cells.