Molecular mechanisms of phosphoantigen sensing by human gamma delta T cells

Gamma delta T-cells have co-evolved in vertebrates alongside T-cells and B cells for ~500 million years, and mediate critical aspects of host defense against microbial infection and tumourigenesis. However, the molecular mechanisms by which they sense target cell dysregulation are largely unclear. This project focusses on the most prevalent human Tcell subset ( T-cells), which represent a highly prevalent innate-like population in peripheral blood that can respond rapidly in bacterial/mycobacterial infection and to cancer cells, by detecting elevated levels of pyrophosphate antigens (P-Ag) in target cells. The project will probe key molecular interactions underpinning this sensing system, specifically T cell receptor interaction with the P-Ag 'sensor' BTN3A1 and a direct ligand BTN2A1. A range of approaches will be employed, structural biology and protein modelling approaches, bioinformatic analyses, cellular immunology assays, and finally immunohistochemistry. This should provide a comprehensive molecular mechanism for T cell antigen recognition, and a knowledge-base for future rational exploitation of T cell in anti-cancer and anti-microbial immunotherapy.