HEDGEMOD - HEDGEhog signalling MODes of immune cells in health and disease

Our understanding of how complex immune responses are guided by signalling pathways is incomplete. We study Hedgehog signalling - a classical cell-cell communication system that controls embryonic development and adult tissue maintenance in vertebrates. Interestingly, we found that T cells have adapted morphogenic Hedgehog signalling towards a cell-autonomous pathway downstream of the T cell receptor. Which immune cells utilise the pathway and elemental signalling characteristics remain elusive. Our research programme has two key objectives: - Use a dynamic in vivo reporter of Hedgehog signalling activity and spatial transcriptomics to determine the cohort of immune cells that are dependent on the Hedgehog pathway in homeostasis and during infection and cancer challenge. A series of immune cell-specific knockout models we have generated will dissect individual roles of Hedgehog signalling in immune cell subsets. - Define the unique mechanistic pathway adaptations of Hedgehog signalling in T cells. Bespoke transgenic mouse models and molecular, proteomics and imaging approaches using nanobodies will be used to understand Hedgehog ligand processing and signal transduction and the immune specific target genes of the pathway that interface biological output. Taken together, the proposed work will reveal fundamental new biology and detail unique therapeutic entry points against infection and cancer.