Exploring innate-like and adaptive gamma delta T cell paradigms in health and disease

γδ T-cells have been retained in vertebrates for ~500million years, and are of increasing therapeutic interest, but their mode of ligand recognition and immunological niche has remained largely mysterious. Here we build on the emergence of parallel innate-like and adaptive human γδ T-cell paradigms to address unresolved ‘keystone’ questions in γδ T-cell biology. Firstly, we will exploit multidisciplinary approaches to explore the diversity of innate-like and adaptive γδ biology in different tissues, their coordination with other immune responses, and how these change in disease states such as inflammation and cancer. Secondly, we will identify molecular targets of γδ-TCRs from innate-like subsets and structurally characterise their TCR/ligand interactions and cellular/molecular recognition mechanisms, focussing significantly on the strong emergence of Butyrophilin family molecules as critical TCR-ligands for such populations. Thirdly we will exploit cytomegalovirus infection as a unique human model to identify novel ligands for antigen-experienced adaptive-like γδ T-cell subsets. Finally, we will develop and apply new methodology to image and phenotype distinct human γδ T-cell subsets in solid tissues, using multispectral immunofluorescence and digital spatial profiling. This programme should help revolutionise our understanding of γδ T-cells, and provide a solid foundation for ongoing efforts to therapeutically harness the γδ T-cell compartment.