Decoding adaptive-like γδ T-cell recognition in human herpesvirus infection

Our work has revised understanding of human γδ T-cells, establishing that in addition to innate-like subsets, the compartment unexpectedly includes a major adaptive-like component. Adaptive-like γδ T-cells are an evolutionarily ancient, MHC-unrestricted arm that acts as ‘Nature’s CAR-T-cells’, driving protection against pathogens and tumours. However, an understanding of how changes denoting infection and cancer are ‘encoded’ in antigenic ligands, and how such alterations are ‘deciphered’ by the γδ-TCR - a holy grail in the field - is currently lacking. This proposal focusses a multidisciplinary collaborative team on tackling this challenge, exploiting Cytomegalovirus and Epstein Barr Virus as human models of microbial stress. Leveraging virology, γδ T-cell immunobiology, ligand identification, and molecular skillsets, we will define how γδ-TCRs sense virally-induced signatures of ‘altered-self’ and how this relates to γδ TCR-mediated recognition of ‘transformed-self’. Our programme will profoundly shift current paradigms of γδ T-cell immunobiology, establishing adaptive subsets as sophisticated sensors of stress-induced ligand alterations. Collectively, it will reveal new molecular targets, uncover distinct principles of TCR/ligand recognition, and define novel antigen-specific γδ-TCR clonotypes. In doing so, the outcomes will create a platform for development of new classes of γδ-TCR-based biotherapeutics and engineered cellular therapies with broad applicability for infection and cancer.